molecules Review
Linking Aromatic Hydroxy Metabolic Functionalization of Drug Molecules to Structure and Pharmacologic Activity Babiker M. El-Haj 1, * 1 2 3
*
ID
, Samrein B. M. Ahmed 2 , Mousa A. Garawi 1 and Heyam S. Ali 3
Department of Pharmaceutical Sciences, College of Pharmacy, Ajman University, Ajman, UAE;
[email protected] College of Medicine, Sharjah Institute for Medical Research, University of Sharjah, Sharjah, UAE;
[email protected] Department of Pharmaceutics, Dubai Pharmacy College, Dubai, UAE;
[email protected] Correspondence:
[email protected]; Tel.: +9715-6-720-4338
Received: 7 July 2018; Accepted: 13 August 2018; Published: 23 August 2018
Abstract: Drug functionalization through the formation of hydrophilic groups is the norm in the phase I metabolism of drugs for the modification of drug action. The reactions involved are mainly oxidative, catalyzed mostly by cytochrome P450 (CYP) isoenzymes. The benzene ring, whether phenyl or fused with other rings, is the most common hydrophobic pharmacophoric moiety in drug molecules. On the other hand, the alkoxy group (mainly methoxy) bonded to the benzene ring assumes an important and sometimes essential pharmacophoric status in some drug classes. Upon metabolic oxidation, both moieties, i.e., the benzene ring and the alkoxy group, produce hydroxy groups; the products are arenolic in nature. Through a pharmacokinetic effect, the hydroxy group enhances the water solubility and elimination of the metabolite with the consequent termination of drug action. However, through hydrogen bonding, the hydroxy group may modify the pharmacodynamics of the interaction of the metabolite with the site of parent drug action (i.e., the receptor). Accordingly, the expected pharmacologic outcome will be enhancement, retention, attenuation, or loss of activity of the metabolite relative to the parent drug. All the above issues are presented and discussed in this review using selected members of different classes of drugs with inferences regarding mechanisms, drug design, and drug development. Keywords: aromatic hydroxy metabolites; arenolic drug metabolites; metabolic O-dealkylation; metabolic aromatic-ring hydroxylation; primary and auxiliary pharmacophores; auxophores; metabolic modification of drug activity
1. Introduction Phase I metabolism of drugs (also known as the non-synthetic or functionalization phase) is mainly brought about by microsomal enzymes adding hydrophilicity to hydrophobic moieties in drug molecules. In most cases, this is attained metabolically by revealing or introducing the hydrophilic hydrogen-bonding hydroxyl group. Generally, metabolic interference may take place at pharmacophoric and/or auxophoric groups. Accordingly, the location in a drug molecule at which the metabolic change takes place may determine the pharmacologic outcome of the metabolite. In any case, the resulting drug metabolite may be pharmacologically inactive, less active, equiactive, or even more active with respect to the parent drug. In other cases, an inactive parent drug is metabolically converted to the active form, in which case the inactive parent drug is known as a “prodrug”. Cases where the metabolic changes are intermediary in drug activation are also known.
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For some drug metabolites, the pharmacologic outcomes—pharmacodynamic, pharmacokinetic, and toxicologic—prove to be substantially more favorable compared to their parent drugs. In such cases, the metabolites were developed into drugs of their own rights. In this review, such drug metabolites are referred to as “metabolite drugs”. Generally, in drug development, the pharmacophoric or auxophoric roles of functional groups in lead drug compounds or drug prototypes are modified in the synthetic laboratory in some way. The introduction of a group in the framework, the reduction of a group to framework status, or the replacement of a group by another are the main strategies followed. Through biotransformation, the body may play an analogous in vivo role by changing pharmacophoric and/or auxophoric groups into others, or by introducing groups at certain positions of the drug molecule with concomitant changes in pharmacodynamic and/or pharmacokinetic properties of the metabolite relative to the parent drug. Such metabolic changes of a drug molecule may lead to a variety of pharmacologic outcomes. The dependence of the metabolic change on the structure of the drug molecule and the pharmacologic outcomes of the resulting metabolites are the subjects of this review. In its interactions with drugs, the body discriminates between different chemical structures, as well as between stereoisomers of the same drug. In stereoisomers of the same drug, the atoms and groups have the same connectivity but differ in spatial arrangement, i.e., three-dimensional (3D) structures. Drug molecules that contain chiral centers exist as stereoisomers known as enantiomers. Enantiomers are designated in two ways: (a) as R or S, depending on the atomic numbers of the atoms bonded to the chiral center, or (b) as dextro (+) or levo (−) depending on the direction in which they rotate the plane of polarized light. Enantiomers of a chiral drug have identical chemical and physical properties; however, they differ in their pharmacodynamic and/or pharmacokinetic properties when they interact with the chiral environment of the body [1]. Where applicable, the pharmacodynamic differences of enantiomers are highlighted for the chiral drugs and their metabolites, which are presented as examples in this review as classes of drugs or as individual drugs. 2. Objective of the Review The objective of this review is to investigate the relationship between the metabolic change and the modification of pharmacodynamic and/or pharmacokinetic properties of drugs in an endeavor to explain when the pharmacologic activity of the metabolite is retained, decreased, lost, or even enhanced with respect to the parent drug. The link between the metabolic functionalization and pharmacologic activity to the structure of the drug is also of prime interest. Such information, as described above, will be useful in drug design when contemplating new drug entities. Additionally, it should be useful in drug development when considering what chemical changes are required in a lead drug compound or prototype for better drug efficacy and metabolic stability. 3. Methodology The inclusion criteria of the selection of drugs to be reviewed include the following: (a) (b)
Drugs that are metabolized by O-dealkylation or aromatic ring hydroxylation; Availability of data regarding the pharmacologic activity of the major metabolite(s). The sources of information include the following:
• • •
The published literature; Drug manufacturers’ data sheets; Reference books on drug metabolism and activity of metabolites.
The selection of the case-study drugs was based on varying the pharmacologic and chemical classes, as described in each section.
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4. Review Review Strategy Strategy 4. Although the the selected selected drugs drugs are are mostly mostly metabolized metabolized by by multi multi routes, routes, only only metabolic metabolic oxidative oxidative Although reactions that result in one chemical functionality, the aromatic hydroxy group, were considered. The reactions that result in one chemical functionality, the aromatic hydroxy group, were considered. representative drugs werewere selected based on both chemical structure and pharmacologic action. Each The representative drugs selected based on both chemical structure and pharmacologic action. study/metabolite(s) case is presented in a figure including the following information subject to Each study/metabolite(s) case is presented in a figure including the following information subject to availability in the literature: availability in the literature:
•• •• ••
The chemical chemical structure structure of of the the drug drug and and metabolite(s), metabolite(s), and and the the enzymes enzymes or or isoenzymes isoenzymes involved; involved; The The status status of of the the pharmacologic pharmacologic activity activity of of the the metabolite; metabolite; The The percentage concentration of the metabolite(s) with respect respectto tothe theparent parentdrug. drug. The percentage concentration of the metabolite(s) with Each parent parent drug drug is is briefly briefly reviewed. reviewed. The The arguments arguments for for the the links links between between metabolic metabolic changes changes Each and pharmacologic activity and structure are discussed for some drug/metabolite cases, as well as as and pharmacologic activity and structure are discussed for some drug/metabolite cases, as well being presented presented in in an an overall overall discussion discussion given given for for all all the the cases cases at at the the end endof ofthe thesection. section. being Metabolites 5. Aromatic Hydroxy (Arenolic) Metabolites Arenolic metabolites metabolites can result result from from one one of of two metabolic reactions: reactions: O-dealkylation of aralkoxy Arenolic groups or hydroxylation hydroxylation of aromatic rings (mainly benzene); in the latter case, the positions of the the hydroxy groups are determined by the prevailing electronic and steric effects on the aromatic ring. The benzene benzenering ringmay maybe bepresent presentininthe thedrug drugmolecule moleculeasas a separate entity (i.e., a phenyl group), The a separate entity (i.e., as as a phenyl group), or or it may be fused to another benzene ring, or to an alicyclic or a heterocyclic ring. When the benzene it may be fused to another benzene ring, or to an alicyclic or a heterocyclic ring. When the benzene described as ring is fused to either an alicyclic or heterocyclic ring, the resulting ring system may be described benzenoid. Arenolic metabolites are are presented presented and and discussed discussed in in Sections Sections 5.1 5.1 and and 5.2. 5.2. benzenoid. 5.1. Arenolic Metabolites Resulting from from the the O-Dealkylation O-Dealkylation of of Aralkoxy Aralkoxy Groups Groups The involves, asas a The metabolic metabolic cytochrome cytochromeP450 P450(CYP)-catalyzed (CYP)-catalyzedO-dealkylation O-dealkylationofofaralkoxy aralkoxygroups groups involves, first step, the hydroxylation of the carbon atom of the alkyl group that is linked to the oxygen atom. a first step, the hydroxylation of the carbon atom of the alkyl group that is linked atom. This is unstable; it breaks spontaneously into two molecules: dealkylated This hydroxylated hydroxylatedmetabolite metabolite is unstable; it breaks spontaneously into two the molecules: the metabolite an alcohol or an a phenol) aldehyde formaldehyde demethylation, dealkylated(e.g., metabolite (e.g., alcohol and or aanphenol) and(e.g., an aldehyde (e.g., after formaldehyde after acetaldehyde after deethylation, etc.)deethylation, [2]. The reaction shown a general case infor Figure 1, where demethylation, acetaldehyde after etc.)is[2]. The for reaction is shown a general casethe in R group1,can be aliphatic or aromatic. Figure where the R group can be aliphatic or aromatic. O-dealkylation of methyl ether
O
R
CH 3
OH
CYP 450 R
Methyl ether
O
O
CH 2
Intermediate
An alcohol or a phenol
OH
R
H
Formaldehyde
C H
O-dealkylation of ethyl ether R R
O
CH 2CH 3
Ethyl ether
OH
OH
CYP 450 R
O
O
CHCH 3
Intermediate
CH 3
Acetaldehyde
C H
Figure 1. 1. Cytochrome P450 (CYP)-catalyzed (CYP)-catalyzed O-dealkylation O-dealkylation of of alkyl alkyl or or aralkyl aralkyl ethers. ethers. Figure Cytochrome P450
The O-dealkylation O-dealkylation of of aralkoxy aralkoxy groups groups results results in in the the formation formation of of arenolic arenolic metabolites metabolites of of varying varying The pharmacologic activities, as is reviewed for the following selected cases: pharmacologic activities, as is reviewed for the following selected cases: (1) Enhancement occurring in in the the opioid opioid narcotic/analgesic narcotic/analgesic drug, codeine, and and its its (1) Enhancement of of activity activity occurring drug, codeine, semisynthetic aryl-methoxy group, group, and and the the semisynthetic and and synthetic synthetic congeners, congeners, all all containing containing an an aryl-methoxy analgesic/antipyretic drug, phenacetin, which contains an aryl-ethoxy group; analgesic/antipyretic drug, phenacetin, which contains an aryl-ethoxy group; (2) Retention of activity by venlafaxine, (a selective-serotonin-reuptake-inhibitor (SSRI) antidepressant, containing an aryl-methoxy group);
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(2) Retention of activity by venlafaxine, (a selective-serotonin-reuptake-inhibitor (SSRI) (3) Attenuation or containing loss of activity by COX1/COX2-inhibitors, -naproxen, indomethacin, and antidepressant, an aryl-methoxy group); nabumetone-each containing an aryl-methoxy group. (3) Attenuation or loss of activity by COX1/COX2-inhibitors, -naproxen, indomethacin, and nabumetone-each containing an aryl-methoxy group. 5.1.1. Metabolic Aralkoxy Group Cleavage Resulting in the Enhancement of Pharmacologic Activity: Opioids and Phenacetin 5.1.1. Metabolic Aralkoxy Group Cleavage Resulting in the Enhancement of Pharmacologic Activity: Opioids and Phenacetin Opioids Opioids Opioid drugs can be defined as those acting on the various types of opioid receptors (mu, kappa, Opioid can be defined as those acting on the various typesis of opioid receptors (mu, and delta) to drugs produce a range of biologic effects. Mu-receptor stimulation associated with analgesic kappa, and delta) to produce a range of biologic effects. Mu-receptormotility stimulation is associated (antinociceptive) effects, respiratory depression, reduced gastrointestinal (constipation), and with analgesic (antinociceptive) effects, respiratory depression, reduced gastrointestinal motility euphoric and dependence effects, while kappa-receptor stimulation is associated with analgesia, (constipation), euphoric and dependence effects, psychomimeticand effects, dysphoria, and diuresis [3,4]. while kappa-receptor stimulation is associated with For analgesia, psychomimetic effects, dysphoria, and diuresis opioid [3,4]. drugs can be classified with the sake of discussion, methoxy-group-containing For the sake ofsource discussion, methoxy-group-containing drugs can be origin classified withcodeine), regards regards to their and chemical build-up. Sourceopioid includes natural (e.g., to their source(e.g., and chemical build-up. Source includes(e.g., natural origin (e.g., codeine), semisynthetic semisynthetic codeine congeners), and synthetic tramadol). Tramadol is considered to be (e.g., codeine congeners), and synthetic (e.g., tramadol). Tramadol is considered to be a synthetic a synthetic codeine congener since it was developed using codeine as template. Chemically, codeine codeine congener since it was developed using codeine asor template. Chemically, codeine its and its semisynthetic congeners are classified as pentacyclic tetracyclic morphinans (Figureand 2). On semisynthetic congeners as pentacyclic or tetracyclic morphinans the other the other hand, tramadolare is classified a non-morphinan bicyclic opioid devoid of rings(Figure B and 2). C, On as shown in hand, tramadol is a non-morphinan bicyclic opioid devoid of rings B and C, as shown in Figure 2. Figure 2. NCH3
NCH3
B C A
E O
N(CH3)2
B C D
A
A
D H3CO
Pentacyclic morphinan
Tetracyclic morphinan
(Codeine and its congeners)
(Levomethorphan)
HO
Tramadol
Figure Chemicalclassification classification of methoxy-group-containing morphinan and non-morphinan Figure 2. 2. Chemical of methoxy-group-containing morphinan and non-morphinan opioids. opioids.
(1) Codeine (1) Codeine Codeine Codeine (Figure (Figure 3) 3) is is an an opium opium alkaloid; alkaloid; it it is is the the methyl methyl ether ether of of morphine morphine and and is is present present in in opium in a 1–3% concentration [5]. It is obtained semisynthetically on a large scale by the methylation opium in a 1–3% concentration [5]. It is obtained semisynthetically on a large scale by the methylation of being only about 0.1% as active as morphine [6]. of morphine. morphine. Codeine Codeineisisaaweak weakmu-receptor mu-receptoragonist, agonist, being only about 0.1% as active as morphine The analgesic activity of codeine is mainly attributed to its metabolites. Codeine is metabolized as per [6]. The analgesic activity of codeine is mainly attributed to its metabolites. Codeine is metabolized the pathways shown in Figure to codeine-6-glucuronide, morphine, and norcodeine. The resulting as per the pathways shown in3Figure 3 to codeine-6-glucuronide, morphine, and norcodeine. The morphine is further metabolized to the 3and 6-glucuronide conjugates [7,8]. As indicated in Figure 3, resulting morphine is further metabolized to the 3- and 6-glucuronide conjugates [7,8]. As indicated reports in the literature on the concentrations of codeine metabolites are variable. Further, reports in Figure 3, reports in the literature on the concentrations of codeine metabolites are variable. Further, on the mu-receptor affinity andaffinity analgesicand activity of codeine metabolites are even contradictory. It is reports on the mu-receptor analgesic activity of codeine metabolites are even acontradictory. longstandingItbelief that the mu-receptor affinity and analgesic activity of codeine are mediated is a longstanding belief that the mu-receptor affinity and analgesic activity of codeine through its metabolite, which has anwhich affinity for mu-opioid 200-fold greater are mediated through itsmorphine, metabolite, morphine, has anthe affinity for thereceptor mu-opioid receptor 200than that of codeine [9]. analgesic activity of codeine was to be largely due itslargely metabolite fold greater than that ofThe codeine [9]. The analgesic activity ofsuggested codeine was suggested to be due morphine [9–12]. However, of late, Vree et al. (2000) developed a different view of codeine’s affinity its metabolite morphine [9–12]. However, of late, Vree et al. (2000) developed a different view of to the mu-opioid and its analgesic authorsactivity. argued The that authors the analgesic activity of codeine’s affinityreceptor to the mu-opioid receptoractivity. and itsThe analgesic argued that the codeine was due toofitscodeine glucuronide than to conjugate its O-desmethyl [13]. analgesic activity was conjugate due to itsrather glucuronide rathermetabolite, than to itsmorphine O-desmethyl The literature’s evidence on the mu-receptor affinity and the analgesic activity of metabolite, morphinecontradictory [13]. codeine its metabolites are weighed in the section.affinity and the analgesic activity of Theand literature’s contradictory evidence ondiscussion the mu-receptor It may be of interest to note that codeine’s metabolic pathways codeine and its metabolites are weighed in the discussion section. cover almost the entire spectrum of biological activity, including reactions that aremetabolic augmenting, activating, inactivating, and attenuating It may be of interest to note that codeine’s pathways cover almost the entire spectrum of the analgesicactivity, activity of the metabolite with that respect the parent drug. biological including reactions areto augmenting, activating, inactivating, and
attenuating of the analgesic activity of the metabolite with respect to the parent drug.
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Molecules 2018, 23, x FOR PEER REVIEW Molecules 2018, 23, x FOR PEER REVIEW NCH3 Molecules 2018, 23, x FOR PEER REVIEW
NCH3
9H NCH3 1 14 NCH 8 9H3 13 NCH6 1 14 9 H 3 8 O 513 8 H3CO 13 149HH6 OH 1 14513 6 8 3 O H3CO Codeine OH 13H O 5 6 OH H3CO 3 H 5 Codeine 3 OCYP2B7OH H(50-70%) 3CO H
9H
14
CYP2D6 0-15% CYP2D6 CYP2D6 0-15% CYP2D6 0-15% 0-15%
Codeine CYP2B7 Codeine (50-70%) Codeine-6-glucuronide
HO HO HO HO
NCH3 NCH
9H3 13 NCH6 14 9 H3 O 5 13 14 9HH6 OH 145 13 6 O OH Morphine 13H O 5 6 OH H
Morphine O 5 OH H Morphine Morphine
%) (60 ) 0% (6CYP2B7 ) % 0 (6 ) % 0 CYP2B7 ((56-10 %) CYP2B7 (5CYP2B7 -10% ) (5-10 %) (5-10 %)
Morphine-3glucuronide Morphine-3(inactive) glucuronide Morphine-3glucuronide Morphine-3(inactive) glucuronide (inactive) Morphine-6(inactive) glucuronide Morphine-6(active) glucuronide Morphine-6glucuronide (active) Morphine-6glucuronide (active) (active)
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(50-70%) CYP2B7 (active) CYP2B7 (50-70%) Codeine-6-glucuronide
Codeine-6-glucuronide (active)Figure 3. Metabolic pathways of codeine. Figure 3. Metabolic pathways of codeine. Codeine-6-glucuronide (active) (active) Figure 3. Metabolic pathways of codeine.
(2)
(2) Codeine Congeners
Codeine Congeners
Figure 3. Metabolic pathways of codeine. Figure 3. Metabolic pathways of codeine.
(2) Codeine Codeine synthetic Congeners pentacyclic-morphinan congeners include hydrocodone, oxycodone, and the (2) Codeine Congeners Codeine synthetic pentacyclic-morphinan congeners include hydrocodone, oxycodone, and the tetracyclic morphinan congener, levomethorphan, which all have 3-arylmethoxy groups Figures (2) Codeine Congeners synthetic pentacyclic-morphinan congeners include hydrocodone, oxycodone, and4–6. the Codeine synthetic pentacyclic-morphinan congeners include hydrocodone, oxycodone, and the On the other hand, tramadol (Figure 6) may be considered a non-morphinan codeine analog since its 4–6. tetracyclic morphinan congener, levomethorphan, which all have 3-arylmethoxy groups Figures tetracyclic morphinan congener, levomethorphan, which all have 3-arylmethoxy groups Figures 4–6. Codeine synthetic pentacyclic-morphinan congeners include hydrocodone, oxycodone, andin the tetracyclic morphinan congener, levomethorphan, which all have 3-arylmethoxy groups Figures 4–6. development was based on codeine as template. Tramadol contains an arylmethoxy group a since On the hand, tramadol maybebeconsidered considered a non-morphinan codeine Onother the other hand, tramadol(Figure (Figure 6) may a non-morphinan codeine analog analog since its tetracyclic morphinan congener, levomethorphan, which alla have 3-arylmethoxy groups Figures 4–6. On the other hand, tramadol (Figure 6) may be considered non-morphinan codeine analog since its position reminiscent to that of codeine. While hydrocodone, oxycodone, and tramadol are currently development was was based based on codeine contains an arylmethoxy group in a in a its development codeineas astemplate. template.Tramadol Tramadol contains an arylmethoxy group On the other hand, tramadol (Figure 6)as may be considered a non-morphinan codeine analog sincein itsa development was based onof codeine template. Tramadol contains an arylmethoxy group clinically used in pain management [14,15], levomethorphan has never been used. The four drugs are position reminiscent to that codeine. While hydrocodone, oxycodone, and tramadol are currently position reminiscent tobased that of codeine. While hydrocodone, oxycodone, and tramadol are currently development was on codeine as template. Tramadol contains an arylmethoxy group in position reminiscent tomanagement that of codeine. hydrocodone, has oxycodone, and tramadol are drugs currently metabolized byinthe isozyme CYP2D6 to While their corresponding O-desmethyl phenolic counterparts, asa clinically used pain [14,15], levomethorphan never been used. The four are clinically used in pain management [14,15], levomethorphan has never been used. The four drugs position tomanagement that of Figures codeine. While hydrocodone, oxycodone, andused. tramadol are currently clinically used inthe pain [14,15], levomethorphan has never been The four drugs are shown inreminiscent thebycorresponding [16–18]. Due to their substantially higher mu-receptor metabolized isozyme CYP2D6 to4–7 their corresponding O-desmethyl phenolic counterparts, as are metabolized by the isozyme CYP2D6 to their corresponding O-desmethyl phenolic counterparts, clinically usedby inthe pain management [14,15], levomethorphan has never been used. The four drugs are metabolized isozyme CYP2D6 to4–7 their corresponding O-desmethyl phenolic counterparts, as affinities, their higher analgesic activities to their parent drugs [15,16], shown in and the accordingly, corresponding Figures [16–18]. Due to compared their substantially higher mu-receptor metabolized by the isozyme CYP2D6 to their corresponding O-desmethyl phenolic counterparts, as as shown in the corresponding Figures 4–7 [16–18]. Due to their substantially higher mu-receptor shown in the corresponding Figures 4–7 [16–18]. Due to their substantially higher mu-receptor the four phenolic metabolites developed drugscompared of their own rights. Presumably, the affinities, and accordingly, theirwere higher analgesicinto activities to their parent drugs [15,16], shown in and the corresponding Figures 4–7 [16–18]. Due their higher mu-receptor affinities, and accordingly, their higher analgesic activities compared to their parent drugs [15,16], affinities, accordingly, their higher analgesic activities compared to their parent drugs [15,16], increase mu-receptor affinity and analgesic activity is atoresult ofsubstantially theown phenolic hydroxy groups in the four inphenolic metabolites were developed into drugs of their rights. Presumably, the affinities, and accordingly, their higher analgesic activities compared to their parent drugs [15,16], the four phenolic metabolites were developed into drugs of their own rights. Presumably, the increase the four-metabolite four inphenolic metabolites were developed into drugs ofwhy their own rights. Presumably, the drugs. We present a possible explanation of this is the case in the discussion increase mu-receptor affinity and analgesic activity is a result of the phenolic hydroxy groupsthe in the four in phenolic metabolites were developed into drugs of the their own rights. Presumably, increase mu-receptor affinity and analgesic activity is a result of the hydroxy groupsthe in section. in mu-receptor affinity and analgesic isexplanation a result of phenolic hydroxy groups in the the four-metabolite drugs. We present aactivity possible of why thisphenolic is the case in the discussion increase in mu-receptor affinity and analgesic activity is a result of the phenolic hydroxy groups in the four-metabolite drugs. We present a possible explanation of why this the case in the discussion four-metabolite drugs. We present a possible explanation of why this is theiscase in the discussion section. section. NCH3 case in the discussion the four-metabolite drugs. We present a possible explanation of why this is the NCH NCH3 3 section. 9 section. 9 NCH 9 3 NCH NCH 1
3
14 NCH3 9 13 NCH3 1 14 9 O 5 H3CO 13 1413 9 1 O14513 3 H3COHydrocodone O 13 H CO 3 5
CYP2D6
6 O 6 6O
CYP2D6 CYP2D6 CYP2D6
3 6O O 5 3 H3CO Hydrocodone O
3
1
14 NCH3 9 13 NCH3 6 1 14 9 O 5 HO 13 O 1413 9 6 13 1 14 O 5 3 HOHydromorphone 6O O 13 HO 3 5 6O O 5 3 HO Hydromorphone O
1
14 NCH3 9 13 NCH3 6 1 14 9 UGT27B O 3 Gluc-O 1 O 14513 9 UGT27B 6 13 1 O145 3 UGT27B Gluc-O 6O Hydromorphone 13 O 5 3 Gluc-O glucuronide 6O O 5 3 Hydromorphone Gluc-O O
UGT27B
glucuronide Hydromorphone Figure 4. Metabolic pathways of hydrocodone. Hydromorphone Hydrocodone glucuronide Hydromorphone Hydromorphone Hydrocodone Figure 4. Metabolic pathways of hydrocodone. glucuronide NCH NCH 3 3 Figure 4.4.Metabolic ofhydrocodone. hydrocodone. Figure Metabolic pathways pathways of
NCH3
OH 9 OH of hydrocodone. 9Figure 4. Metabolic pathways 9 OH NCH NCH NCH 3 3 3 1 1 14NCH 14NCH 14NCH CYP2D6 UGT27B 1 3 3 3 9 OH 9 OH 9 OH 13 13 13 NCH3 NCH3 NCH3 1 1 14 9 OH 14 9 OH 6 UGT27B 6 14 9 OH 6 CYP2D6 1 O 5 O 513 O 14513 H3CO 13 14913OH O UGT27BGluc-O 3 149 OH O CYP2D6 HO 13 9 OH O 1 6 6 1 14 13 14 13 1413 6 CYP2D6 HO1 3 UGT27B O 5 13 O 5 O 5 Oxymorphone H3CO 3 Gluc-O Oxymorphone 6O 6O 6O Oxycodone 13 13 13 O 5 O 5 3 glucuronide O HO O 3 5 H3CO 3 O Gluc-O 6 6 6O Oxymorphone O O Oxymorphone 3 5 3 5 O HO O 5 H3CO Oxycodone O Gluc-O 3 O
glucuronide Oxymorphone Figure 5. Metabolic pathways of oxycodone. Oxymorphone Oxycodone glucuronide Oxymorphone Oxymorphone Oxycodone Figure 5. Metabolic pathways of oxycodone. glucuronide NCH NCH 3 3 Figure 5. Metabolic pathways of oxycodone.
B * 9 Figure of oxycodone. Figure5.5.Metabolic Metabolic pathways pathways NCH of oxycodone. NCH3
D * 83 UGT2B7 B 14 3 * NCH 9 A C 8 1B NCH3 D NCH * 9* 3 UGT2B7 CYP2D6 5 14 68 B HO 31A H3CO *D 9*14 UGT2B7 C CYP2D6 1A 8 D 5* 6 3 UGT2B7 C CYP2D6 HOLevorphanol 14 HLevomethorphan 3CO A 5C 6 HO 3 H3CO The ring-letter designation, the carbon-atom and 5 numbering Levomethorphan 6 Levorphanol HO 3 H3CO NCH3
CYP2D6
1
O-glucuronidation
O-glucuronidation O-glucuronidation O-glucuronidation the chiral-center asterisk designation in levomethorphan is the same as for levorphanol. Levomethorphan Levorphanol The ring-letter designation, the carbon-atom Levomethorphan Levorphanolnumbering and the chiral-center asterisk designation in levomethorphan is thenumbering same as forand levorphanol. The ring-letter designation, the carbon-atom the chiral-center Figure 6. Metabolic pathways of levomethorphan. asterisk designation in levomethorphan is thenumbering same as for levorphanol. The ring-letter designation, the carbon-atom and the chiral-center Figure 6. in Metabolic pathways of levomethorphan. asterisk designation levomethorphan is the same as for levorphanol.
Figure 6. Metabolic pathways of levomethorphan. Figure 6. Metabolic pathways of levomethorphan.
Figure 6. Metabolic pathways of levomethorphan.
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CH3 H3CO
2 1
* *
N
N
CH3
CH3
HO CYP2D6
CH3
glu-O UGT2B7
HO
Tramadol
CH3
CH3
N
HO
HO
O-Desmethyltramadol (active)
O-Desmethyltramadol glucuronide (inactive)
Figure 7. Metabolic pathways of tramadol.
The subject subjectofofstereochemistry stereochemistry is paramount of paramount importance considering drug structure– The is of importance whenwhen considering drug structure–activity activity relationship of chiral drugs. Of the four codeine congeners, tramadol and levorphanol relationship of chiral drugs. Of the four codeine congeners, tramadol and levorphanol present the most present the most interesting features. interesting features. of the the Morphinan Morphinan Opioids Opioids Stereochemistry of The stereochemistry stereochemistryofof pentacyclic morphinan opiates, to which morphine and thethe pentacyclic morphinan opiates, to which belong belong morphine and codeine, codeine, is complicated by their rigid ring and the of multi-chiral centers. Morphine is complicated by their rigid ring system andsystem the presence ofpresence multi-chiral centers. Morphine and codeine and codeine five chiral centers, asby indicated by the wedged bonds 3. in Assigning Figure 3. Assigning both containboth five contain chiral centers, as indicated the wedged bonds in Figure absolute absolute configuration to each chiral and then absolute an overall absolute configuration to either configuration to each chiral center andcenter then an overall configuration to either a codeine or a codeine ormolecule a morphine a challenge. With aoftotal number of 32the enantiomers, the task is morphine is a molecule challenge.isWith a total number 32 enantiomers, task is overwhelming. overwhelming. the purpose designation chirality, optical activity may be used. In However, for theHowever, purpose offor designation of of chirality, opticalofactivity may be used. In multi-chiral center multi-chiraloptical centeractivity molecules, activity is an function ofcomponent the rotations at the component molecules, is anoptical additive function ofadditive the rotations at the asymmetric centers. asymmetric morphine,member the most important member of the pentacyclic morphinans, In morphine,centers. the mostInimportant of the pentacyclic morphinans, the chiral centers at C5, the C6, chiral centers at C5, C6, and C9 (Figure 3) rotate the plane of polarized light to the left (levo (−)) while and C9 (Figure 3) rotate the plane of polarized light to the left (levo (−)) while the remaining centers at the remaining at right C13 and C14 do[19]. so to the right on (dextro (+)) [19]. Depending the overall C13 and C14 docenters so to the (dextro (+)) Depending the overall optical rotation,on the analgesic optical rotation, analgesicisactivity of natural morphine[20]. is attributed to levomorphine [20]. activity of naturalthe morphine attributed to levomorphine As shown in Figure 6, the tetracyclic tetracyclic morphinan, levorphanol, has two chiral centers at C9 and addition to to exhibiting exhibitingcis/trans cis/trans isomerism. Despite the the fact fact that that the the B/C B/C cis C14, in addition cis (14R) (14R) configuration configuration B/C trans is two-fold less active than the B/C trans isomer, isomer, it it is the one that is clinically used as a narcotic ofof the two chiral centers in analgesic [21]. The The additive additiveoptical opticalrotation rotationofofthe theplane planeofofpolarized polarizedlight light the two chiral centers levorphanol must bebe to to the in levorphanol must theleft, left,thus thusaccounting accountingfor forthe theorigin origin of of the the prefix levo. The The fact that enantiomers of chiral drugs may have different actions is demonstrated by the dextro counterpart of levorphanol, i.e., dextrophan, which is used as an antitussive, and is devoid of the narcotic analgesic levo enantiomer enantiomer [22]. [22]. activity characteristic of the levo The non-morphinan non-morphinan opioid drug, tramadol, tramadol, contains contains two chiral centers, as indicated by asterisks accordingly, itit exists exists in in four four enantiomeric enantiomeric forms. forms. In addition, addition, because it contains a in Figure 7, and accordingly, cyclohexane ring, tramadol exists exists as as cis/trans cis/trans isomers. Despite the fact that tramadol is marketed as isomers. Despite the isomer, its its enantiomers enantiomers and and active active O-desmethyl O-desmethyl metabolite metabolite have have significant significant the racemate of the cis isomer, their analgesic analgesic mechanism mechanism of of action. action. Specifically, Specifically, the the 1S,2S-( 1S,2S-(−) selectivity in their −) enantiomer inhibits norepinephrine reuptake, while the the 1R,2R-( 1R,2R-(−) −) enantiomer enantiomer inhibits inhibits 5-HT 5-HT (serotonin) reuptake to activity. On the the other other hand, hand, the the dextrorotatory dextrorotatory O-desmethyltramadol O-desmethyltramadol produces a produce analgesic activity. analgesic activity activity than than tramadol tramadol via via stimulating stimulating the the mu mu receptors receptors [23]. [23]. six-fold greater analgesic Discussion of Opioids The metabolic of the opioids is discussed metabolicO-demethylation O-demethylation of methoxy-group-containing the methoxy-group-containing opioids is separately discussed because of the availability of substantial supportive evidence. separately because of the availability of substantial supportive evidence. A number of theories were proposed to account for the role of the the phenolic–hydroxy phenolic–hydroxy group in mu-receptor interaction interaction and and the the consequent consequent production production of of analgesia. analgesia. When discussing the structure–activity relationship relationship of opioids, Foye (2013) [24] classified opioid drugs into two categories according to the pharmacophore responsible for mu-receptor interaction: the rigid multicyclic (morphinan) opioids (exemplified by morphine, codeine, and codeine congeners), and the flexible opioids (exemplified by 4-arylpyridinepethidine). To the latter category,
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the rigid multicyclic (morphinan) opioids (exemplified by morphine, codeine, and codeine congeners), 7 of 29 by 4-arylpyridinepethidine). To the latter category, we may7 add of 29 arylcyclohexylmethylamine, which is found in tramadol. structuresThe of the three categories are we may add arylcyclohexylmethylamine, which is found The in tramadol. structures of the three we may add arylcyclohexylmethylamine, which is found in tramadol. The structures of the three depicted in Figure 8. categories are depicted in Figure 8. categories are depicted in Figure 8. Molecules 2018, 23, x FOR PEER REVIEW and the 2018, flexible (exemplified Molecules 23, xopioids FOR PEER REVIEW
NCH3 N
NCH3 H
N
B D
H B D C E A C OE H
A
O
4
1N
R
4
1N
R
4-Arylpiperidine 4-Arylpiperidine
H
Morphinan Morphinan
H H
Arylcyclohexyl dimethylmethylamine Arylcyclohexyl dimethylmethylamine
Figure Figure 8. 8. Structures Structures of of the the opioid opioid drug drug pharmacophores. pharmacophores. Figure 8. Structures of the opioid drug pharmacophores.
Foye (2013) [24] argued the importance of a phenolic–hydroxy group on ring A (Figure 8) to the Foye [24] the importance of group on (Figure to Foye (2013) (2013) [24] argued argued importance of aaofphenolic–hydroxy phenolic–hydroxy group on ring ring A A opioids (Figure 8) 8) to the the mu-receptor interaction and the analgesic activity the rigid multicyclic morphinan such as mu-receptor interaction and analgesic activity of the rigid multicyclic morphinan opioids such as mu-receptor and analgesic activity of the rigid multicyclic morphinan opioids such morphine andinteraction the O-desmethyl metabolites of codeine congeners. The author also maintained thatas a morphine and the O-desmethyl metabolites of codeine congeners. The author also maintained that a morphine and the O-desmethyl metabolites of codeine congeners. The author also maintained that phenolic–hydroxy group is not a requirement for the mu-receptor interaction and analgesic activitya phenolic–hydroxy group is not a requirement for the mu-receptor interaction and analgesic activity of phenolic–hydroxy group is not opioids. a requirement for the mu-receptor interaction and analgesic of the flexible non-morphinan It should be noted that none of the latter groups ofactivity drugs the flexible non-morphinan opioids. It should be noted that none ofnone the latter groups of drugs of contains of the flexible non-morphinan opioids. It should be noted that of the latter groups contains a phenolic hydroxy group and that aromatic-ring hydroxylation is not reporteddrugs as a acontains phenolica hydroxy group and that aromatic-ring hydroxylation is not reported as a metabolic route phenolic hydroxy metabolic route for any of them.group and that aromatic-ring hydroxylation is not reported as a for any of them. metabolic forof any of them.OH binding liability” for the flexible opioids [24] may be contested Foye’sroute theory “phenolic Foye’s theory of “phenolic OH liability” for [24] contested Foye’s theory of “phenolic OH binding binding liability” for the the flexible flexible opioids opioids [24] may may be be contested based on observations from the metabolic activity of O-desmethyltramadol (a metabolite of tramadol; based on observations from from the the metabolic metabolic activity activity of of O-desmethyltramadol O-desmethyltramadol (a (a metabolite metabolite of of tramadol; tramadol; based on observations Figure 7) and ketobemidone (an analog of pethidine; Figure 9). Both drugs can be categorized as nonFigure 7) and ketobemidone (an analog of pethidine; Figure 9). Both drugs can be categorized as Figureflexible 7) and ketobemidone (anopioids. analog of pethidine; Figure 9). Both drugs be categorized as nonrigid non-morphinan O-Desmethyltramadol exhibits a can 200-fold increase in munon-rigid flexible non-morphinan opioids. O-Desmethyltramadol exhibits a 200-fold increase in rigid flexible non-morphinan opioids. O-Desmethyltramadol a 200-fold mureceptor affinity and analgesic activity relevant to tramadol [25].exhibits Ketobemidone, onincrease the otherinhand, mu-receptor affinity and analgesic activity relevant to tramadol [25]. Ketobemidone, on the other hand, receptor affinity and analgesic activity tramadol [25]. Ketobemidone, on the other hand, has a four-fold mu-receptor affinity andrelevant analgesictoactivity compared to pethidine [26]. The enhanced has aa four-fold mu-receptor affinity and analgesic activity compared to pethidine [26]. The enhanced has four-fold mu-receptor affinity and analgesic activity compared to pethidine [26]. The enhanced mu-receptor affinity and analgesic activity of both O-desmethyltramadol and ketobemidone can be mu-receptor affinity and activity of O-desmethyltramadol and ketobemidone can mu-receptor affinity and analgesic analgesic activitywhich of both both O-desmethyltramadol and can be be attributed to the phenolic hydroxy group, is in a position reminiscent to ketobemidone that of morphine. attributed to the phenolic hydroxy group, which is in a position reminiscent to that of morphine. attributed to the phenolic hydroxy group, which is in a position reminiscent to that of morphine. 4
(CH3)2N (CH3)2N H3CO H3CO
3 4 5 2 3 1 65 2 1 OH 6 OH
(1R,2R)-Tramadol (1R,2R)-Tramadol
(CH3)2N (CH3)2N HO HO
2 2
CH3
CH3
CH N 3
CH3 N
N
1 1OH OH
(1R,2R)-O-Desmethyltramadol (1R,2R)-O-Desmethyltramadol
N O
O O
O
Pethidine Pethidine
HO HO
O O
Ketobemidone Ketobemidone
Figure 9. Tramadol/O-desmethyltramadol and pethidine/ketobemidone. Figure9.9. Tramadol/O-desmethyltramadol Tramadol/O-desmethyltramadol and and pethidine/ketobemidone. pethidine/ketobemidone. Figure
Another opioid drug–receptor interaction theory was suggested by Beckett and Casy (1959) [27] Another opioid drug–receptor interaction theory was suggested by Beckett and Casy (1959) [27] who Another stated that the drug–receptor macromolecule with which the was analgesic interacts has, or a certain opioid interaction theory suggested by Beckett andattains, Casy (1959) [27] who stated that the macromolecule with which the analgesic interacts has, or attains, a certain conformation intothe which the phenolicwith group mustthe fit before the interacts biologicalhas, effect analgesia) can who stated that macromolecule which analgesic or (of attains, a certain conformation into which the phenolic group must fit before the biological effect (ofmoiety, analgesia) can occur. A “three-point” attachment of the macromolecule to a substrate’s flat aromatic its basic conformation into which the phenolic group must fit before the biological effect (of analgesia) can occur. A “three-point” attachment of the macromolecule to a substrate’s flat aromatic moiety, its basic center, and its hydrocarbon area was postulated. occur. A “three-point” attachment of the macromolecule to a substrate’s flat aromatic moiety, its basic center, and its hydrocarbon area was postulated. Glucuronide and acetyl derivatives of morphine provide substantiating evidence of the phenolic center, and its hydrocarbon area was postulated. Glucuronide and acetyl derivatives of morphine provide substantiating evidence of the phenolic hydroxy group’s and involvement in strengthening theprovide mu-receptor affinity,evidence and accordingly, the Glucuronide acetyl derivatives of morphine substantiating of the phenolic hydroxy group’s involvement in strengthening the mu-receptor affinity, and accordingly, the analgesic activityinvolvement of the morphinan-opioid drugs contain it, either and intrinsically or metabolically hydroxy group’s in strengthening the that mu-receptor affinity, accordingly, the analgesic analgesic activity of the morphinan-opioid drugs that contain it, either intrinsically or metabolically produced. Further discussion of this point follows. activity of the morphinan-opioid drugs that contain it, either intrinsically or metabolically produced. produced. Further discussion of this point follows. By virtue of its phenolic–hydroxy group at position 3 and alcoholic hydroxy group at position Further discussion of this point follows. By virtue of its 3) phenolic–hydroxy group conjugates: at position 3morphine-3-glucuronide and alcoholic hydroxy group at position 6, morphine (Figure forms two glucuronide and morphine-6By virtue of its phenolic–hydroxy group at position 3 and alcoholic hydroxy group at 6, morphine (Figure (Figure 3). 3) forms glucuronide conjugates: morphine-3-glucuronide and morphine-6glucuronide Whiletwo morphine-6-glucuromide is aconjugates: far more potent mu-receptor agonist and position 6, morphine (Figure 3) forms two glucuronide morphine-3-glucuronide and glucuronide (Figure 3). While morphine-6-glucuromide is aisfar moreofpotent mu-receptor agonist and analgesic than morphine [28–30], morphine-3-glucuronide devoid both effects [31]. Furthermore, analgesic than morphine [28–30], is devoid both [31]. Furthermore, the O-glucuronide conjugates of morphine-3-glucuronide both O-desmethyltramadol (Figureof6) andeffects levorphanol (Figure 7) the devoid O-glucuronide conjugates of both O-desmethyltramadol (Figure 6) and levorphanol (Figure 7) are of mu-receptor agonistic effects, and accordingly, of analgesic activity [32,33]. The above are devoid of mu-receptor agonistic effects, and accordingly, of analgesic activity [32,33]. The above data may be explained based on size and hydrogen-bonding ability differences between the hydroxy data glucuronide may be explained based size and hydrogen-bonding abilityprovided differences thegroup hydroxy and groups. In on morphine, the hydrogen bonding bybetween the 6-OH is and glucuronide groups. In morphine, the hydrogen bonding provided by the 6-OH group is
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morphine-6-glucuronide (Figure 3). While morphine-6-glucuromide is a far more potent mu-receptor agonist and analgesic than morphine [28–30], morphine-3-glucuronide is devoid of both effects [31]. Furthermore, the O-glucuronide conjugates of both O-desmethyltramadol (Figure 6) and levorphanol (Figure 7) are devoid of mu-receptor agonistic effects, and accordingly, of analgesic activity [32,33]. The above be explained Molecules 2018,data 23, x may FOR PEER REVIEW based on size and hydrogen-bonding ability differences between 8 of 29 the hydroxy and glucuronide groups. In morphine, the hydrogen bonding provided by the 6-OH group is important for mu-receptor fitting, andanalgesic thus, analgesic activity. hydroxy moieties, important for mu-receptor fitting, and thus, activity. With With three three hydroxy moieties, the the glucuronide group at position 6 of morphine capableofofestablishing establishingmore morehydrogen hydrogen bonds bonds than glucuronide group at position 6 of morphine is is capable 6-OH. Further Furtherstronger strongerinteractions interactions glucuronide group the receptor mu receptor involve the 6-OH. ofof thethe glucuronide group withwith the mu involve ion– − ) moiety. Such a state of − ion–ion and ion–dipole binding provided by the carboxylate (COO ion and ion–dipole binding provided by the carboxylate (COO ) moiety. Such a state of affairs will affairsprobably will most probably lead mu-receptor to stronger mu-receptor fit,higher and hence, higher analgesic activity of most lead to stronger fit, and hence, analgesic activity of morphine-6morphine-6-glucuronide thanOn morphine. On the other hand, the size (steric) factor thegroup hydroxy glucuronide than morphine. the other hand, the size (steric) factor favors thefavors hydroxy at group at position 3 of morphine to anchor the aromatic ring in its hydrophobic pocket in the mu position 3 of morphine to anchor the aromatic ring in its hydrophobic pocket in the mu receptor, receptor, rather than the considerably bigger glucuronide rather than the considerably bigger glucuronide group. group. analgesic activity activity of of morphine, morphine, 6-acetylmorphine, 6-acetylmorphine, Upon comparing the mu-receptor affinity and analgesic and diamorphine (heroin) (Figure 10), 6-acetylmorphine was found to be the most active of the three than morphine byby a factor of opiates; it is is four four times timesas asactive activeas asmorphine. morphine.Heroin Heroinisisalso alsomore moreactive active than morphine a factor two, butbut less active than 6-acetylmorphine [34,35]. of two, less active than 6-acetylmorphine [34,35].
1
NCH3
NCH3
9 H 8 14
9 H
esterase
13 H3CCO 3
O 5 H
O
6 OCCH3 O
Diamorphine (Heroin)
1
NCH3 8
14
esterase
9 H
1
14
13 HO 3
O
5
8
13 H
6 OCCH3 O
HO 3
O 5 H
6 OH
Morphine
6-Acetylmorphine
Figure Figure 10. 10. Diamorphine, Diamorphine, 6-acetylmorphine, 6-acetylmorphine, and and morphine. morphine.
A plausible explanation of the above data is as follows: being more lipophilic than morphine, A plausible explanation of the above data is as follows: being more lipophilic than morphine, both 6-acetylmorphine and heroin (Figure 10) will cross the blood–brain barrier faster and in higher both 6-acetylmorphine and heroin (Figure 10) will cross the blood–brain barrier faster and in concentrations than morphine. On the other hand, having a free phenolic hydroxy group, 6higher concentrations than morphine. On the other hand, having a free phenolic hydroxy group, acetylmorphine will interact with the opioid mu receptor more efficiently than diamorphine. In 6-acetylmorphine will interact with the opioid mu receptor more efficiently than diamorphine. diamorphine, the free hydroxy group is generated metabolically in the brain by esterase hydrolysis, In diamorphine, the free hydroxy group is generated metabolically in the brain by esterase hydrolysis, which will lead to a delayed effect and reduced efficacy. The effects of morphine and the two which will lead to a delayed effect and reduced efficacy. The effects of morphine and the two acetylated opiates (diamorphine and 6-acetylmorphine) can, therefore, be explained by a acetylated opiates (diamorphine and 6-acetylmorphine) can, therefore, be explained by a combination combination of pharmacodynamic and pharmacokinetic influences. of pharmacodynamic and pharmacokinetic influences. Additional substantiating evidence for the role of the free phenolic hydroxy group may be Additional substantiating evidence for the role of the free phenolic hydroxy group may be obtained from levomethorphan and its O-desmethyl metabolite, levorphanol (Figure 7). These two obtained from levomethorphan and its O-desmethyl metabolite, levorphanol (Figure 7). These two tetracyclic-morphinan opiate drugs lack the 6-hydroxy group, and hence, the ability to form tetracyclic-morphinan opiate drugs lack the 6-hydroxy group, and hence, the ability to form glucuronide glucuronide conjugates at that position; yet, levorphanol has a stronger affinity for the mu receptor conjugates at that position; yet, levorphanol has a stronger affinity for the mu receptor and analgesic and analgesic activity than its parent drug, levomethorphan [36]. activity than its parent drug, levomethorphan [36]. In conclusion, we may summarize the role of the hydroxy group in arenolic opioids in the In conclusion, we may summarize the role of the hydroxy group in arenolic opioids in the following statement: as shown in the opioid pharmacophores in Figure 8, the aromatic rings labeled following statement: as shown in the opioid pharmacophores in Figure 8, the aromatic rings A, present in both morphinan and non-morphinan opioids, are essential components of the labeled A, present in both morphinan and non-morphinan opioids, are essential components of pharmacophore of the opioid–mu-receptor interaction. The high affinity of the arenolic opioids for the pharmacophore of the opioid–mu-receptor interaction. The high affinity of the arenolic opioids for the mu receptor is an indication of a logistic role played by the hydroxy group. Through hydrogen the mu receptor is an indication of a logistic role played by the hydroxy group. Through hydrogen bonding with an adjacent amino-acid residue in the mu receptor, the hydroxy group plays the logistic bonding with an adjacent amino-acid residue in the mu receptor, the hydroxy group plays the logistic role of anchoring the aromatic ring to the assigned hydrophobic pocket in the receptor, thus role of anchoring the aromatic ring to the assigned hydrophobic pocket in the receptor, thus enhancing enhancing both affinity and efficacy. Substantiating evidence to the above statement is provided by both affinity and efficacy. Substantiating evidence to the above statement is provided by the work the work of Sahu et al. (2008) [37] on tetrahydroimidazobenzodiazepinones (the human of Sahu et al. (2008) [37] on tetrahydroimidazobenzodiazepinones (the human immunodeficiency immunodeficiency virus 1 (HIV-1) non-nucleoside reverse transcriptase (NNRT) inhibitors). In this class of compounds, the predominant hydrophobic proper orientation for maximum effect was found to be enhanced by hydrogen bonding and polar interactions. The assertion by Vree et al. of the analgesic activity of codeine being entirely due to its glucuronide conjugate [13] may now be reconsidered in view of the evidence so far presented on the
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virus 1 (HIV-1) non-nucleoside reverse transcriptase (NNRT) inhibitors). In this class of compounds, the predominant hydrophobic proper orientation for maximum effect was found to be enhanced by hydrogen bonding and polar interactions. The assertion by Vree et al. of the analgesic activity of codeine being entirely due to its glucuronide conjugate [13] may now be reconsidered in view of the evidence so far presented on the role of the arenolic hydroxy group in opioid drugs. It is important to emphasize that the conclusion by Vree9etof al. Molecules 2018, 23, x FOR PEER REVIEW 29 was abstract rather than experimental, and as such, may be subject to a difference of opinion. Because Because both both codeine codeine and and tramadol tramadol have have intrinsic intrinsic analgesic analgesic activities, activities, they they can can be be viewed viewed as as prodrugs of morphine and O-desmethyltramadol, respectively, both having sustained-release effects. prodrugs of morphine and O-desmethyltramadol, respectively, both having sustained-release effects. Both Both morphine morphine and and O-desmethyltramadol O-desmethyltramadol are are strong strong mu-receptor mu-receptor agonists agonists used used in in the the management management of of severe severe pain, pain, but but have have the the disadvantages disadvantages of of causing causing dependence dependence and and tolerance. tolerance. Therefore, Therefore, for for the the management of mild-to-moderate pain, it would be advisable to use the corresponding prodrugs, management of mild-to-moderate pain, it would be advisable to use the corresponding prodrugs, codeine of of sustained release. However, some people whowho are codeine and andtramadol, tramadol,which whichhave havethe theadvantage advantage sustained release. However, some people poor CYP2D6 metabolizers do notdo make of the prodrugprodrug sustained-release effect. Foreffect. such are poor CYP2D6 metabolizers not use make usebeneficial of the beneficial sustained-release people, it is advisable to adjust the dose of the parent drug, to administer O-desmethyl metabolites, For such people, it is advisable to adjust the dose of the parent drug, to administer O-desmethyl or to seek alternative therapies. Thetherapies. frequencyThe of the phenotype of poor metabolizers among metabolites, or to seek alternative frequency of the phenotype of poordiffers metabolizers ethnic groups. Less than 1% of Asians, 2–5% of African Americans, and 6–10% of Caucasians are poor differs among ethnic groups. Less than 1% of Asians, 2–5% of African Americans, and 6–10% of metabolizers of CYP2D6 [38–40]. Caucasians are poor metabolizers of CYP2D6 [38–40]. In In addition addition to to the the pharmacodynamic pharmacodynamic receptor receptor interactions interactions of of the the methoxy methoxy opioids opioids (occurring (occurring mainly through their polar hydroxy metabolites), the analgesic effects of hydrophobic mainly through their polar hydroxy metabolites), the analgesic effects of hydrophobic opioid opioid drugs, drugs, as fentanyl, dextropropoxyphene, methadone, and pethidine (Figure 11), were mainly such assuch fentanyl, dextropropoxyphene, methadone, and pethidine (Figure 11), were mainly explained explained by pharmacokinetic effects.drugs Thesecross drugsthe cross the blood–brain efficiently, by pharmacokinetic effects. These blood–brain barrierbarrier more more efficiently, and and accordingly, they reach the mu-receptors in the brain in higher concentrations than the accordingly, they reach the mu-receptors in the brain in higher concentrations than the methoxymethoxy-group-containing [41]. group-containing membersmembers [41]. N O
O
O N
O
O
N
N
N
O
Fentanyl
Dextropropoxyphene
Methadone
Pethidine
Figure 11. 11. Highly Highly hydrophobic hydrophobic opioids. opioids. Figure
Acetanilide/Phenacetin/Paracetamol Acetanilide/Phenacetin/Paracetamol The story of the development of the most commonly used analgesic antipyretic drug, The story of the development of the most commonly used analgesic antipyretic drug, paracetamol, paracetamol, as a metabolite drug of acetanilide and phenacetin is depicted in Figure 12. Both the as a metabolite drug of acetanilide and phenacetin is depicted in Figure 12. Both the latter drugs latter drugs were once used as analgesics and antipyretics. Paracetamol results from phenacetin by were once used as analgesics and antipyretics. Paracetamol results from phenacetin by metabolic metabolic O-deethylation [42], and from acetanilide by metabolic para-hydroxylation of the aromatic O-deethylation [42], and from acetanilide by metabolic para-hydroxylation of the aromatic ring [43]. ring [43]. Compared to its two precursors, paracetamol was found to have superior pharmacologic Compared to its two precursors, paracetamol was found to have superior pharmacologic profiles, profiles, including those of toxicity and therapeutic index [42,43]. The free hydroxy group seems to including those of toxicity and therapeutic index [42,43]. The free hydroxy group seems to give give paracetamol the edge in inhibiting, through hydrogen-bonding interaction, two prostaglandin paracetamol the edge in inhibiting, through hydrogen-bonding interaction, two prostaglandin H2 H2 synthases, now believed to be involved in the mechanism of action of paracetamol [44]. Moreover, synthases, now believed to be involved in the mechanism of action of paracetamol [44]. Moreover, the hydroxy group may play the logistic role of anchoring the aromatic ring in the proper geometric the hydroxy group may play the logistic role of anchoring the aromatic ring in the proper geometric orientation in the enzyme active cavity. orientation in the enzyme active cavity. OH
OH
organic synthesis metabolic-ring hydroxylation
(CH3CO)2O NHCOCH3
Paracetamol NHCOCH3
Acetanilide
metabolic O-deethylation OC2H5
NH2
p-Aminophenol
ring [43]. Compared to its two precursors, paracetamol was found to have superior pharmacologic profiles, including those of toxicity and therapeutic index [42,43]. The free hydroxy group seems to give paracetamol the edge in inhibiting, through hydrogen-bonding interaction, two prostaglandin H2 synthases, now believed to be involved in the mechanism of action of paracetamol [44]. Moreover, the hydroxy group Molecules 2018, 23, 2119 may play the logistic role of anchoring the aromatic ring in the proper geometric 10 of 30 orientation in the enzyme active cavity. OH
OH
organic synthesis (CH3CO)2O
metabolic-ring hydroxylation
NHCOCH3
NH2
Paracetamol
p-Aminophenol
metabolic O-deethylation
NHCOCH3
Acetanilide
OC2H5
Phenacetin
medicinal chemistry
NHCOCH3
Figure 12. to paracetamol. paracetamol. Molecules 2018, 23, x FOR PEER REVIEW Figure 12. From From acetanilide acetanilide to to phenacetin phenacetin to
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Groups Resulting Resulting in in Retaining Retaining Pharmacologic Pharmacologic Activity: Activity: 5.1.2. Metabolic O-Dealkylation of Aralkoxy Groups Venlafaxine/Desvenlafaxine Venlafaxine/Desvenlafaxine Venlafaxine antidepressant in the reuptake inhibitorinhibitor (NSRI) category. Venlafaxineisisanan antidepressant in noradrenaline–serotonin the noradrenaline–serotonin reuptake (NSRI) Being chiralBeing (Figurechiral 13), venlafaxine existsvenlafaxine as R and S enantiomers. category. (Figure 13), exists as RRegarding and S neurotransmitter-reuptake enantiomers. Regarding inhibition, some degree of selectivity wassome observed: theof R-enantiomer actedobserved: as both a noradrenaline and neurotransmitter-reuptake inhibition, degree selectivity was the R-enantiomer serotonin reuptake inhibitor, while the S-enantiomer only as a serotonin reuptake inhibitor [45]. acted as both a noradrenaline and serotonin reuptakeacted inhibitor, while the S-enantiomer acted only as However, the drug is marketed as theHowever, racemate.the drug is marketed as the racemate. a serotonin reuptake inhibitor [45].
* H3CO
Venlafaxine
N
N
OH
OH
*
CYP2D6
*
*
N OH
UGT2B7
HO
*
*
Gluc-O
Desvenlafaxine (O-Desmethylvenlafaxine)
Desvenlafaxine glucuronide
Figure 13. 13. Metabolic Metabolic pathway pathway of of venlafaxine. venlafaxine. Figure
Venlafaxine is mainly metabolized by O-demethylation to equiactive desvenlafaxine (OVenlafaxine is mainly metabolized by O-demethylation to equiactive desvenlafaxine desmethylvenlafaxine; Figure 13). Venlafaxine is further metabolized through N-demethylation and (O-desmethylvenlafaxine; Figure 13). Venlafaxine is further metabolized through N-demethylation glucuronide conjugation to inactive products (Figure 13) [46–48]. Desvenlafaxine was developed into and glucuronide conjugation to inactive products (Figure 13) [46–48]. Desvenlafaxine was developed a drug of its own right and approved by the Food and Drug Administration (FDA) in the United into a drug of its own right and approved by the Food and Drug Administration (FDA) in the States (US) for the treatment of major depressive disorder (MDD), similar to its parent drug, United States (US) for the treatment of major depressive disorder (MDD), similar to its parent drug, venlafaxine, which is used for major depressive and anxiety disorders. However, the European venlafaxine, which is used for major depressive and anxiety disorders. However, the European Medicines Agency (EMA) had second thoughts and did not approve desvenlafaxine as a drug. They Medicines Agency (EMA) had second thoughts and did not approve desvenlafaxine as a drug. They argued that venlafaxine is almost fully metabolized to desvenlafaxine, and that both compounds have argued that venlafaxine is almost fully metabolized to desvenlafaxine, and that both compounds essentially the same pharmacologic and pharmacokinetic profiles; hence, there is no strong reason to have essentially the same pharmacologic and pharmacokinetic profiles; hence, there is no strong use desvenlafaxine as a separate drug [49]. Whether the analogy of the selective activity of the R and reason to use desvenlafaxine as a separate drug [49]. Whether the analogy of the selective activity S enantiomers of venlafaxine may be extended to desvenlafaxine is a subject for experimental of the R and S enantiomers of venlafaxine may be extended to desvenlafaxine is a subject for investigation. experimental investigation. Venlafaxine carries structural similarity to the analgesic drug, tramadol. The latter drug exerts Venlafaxine carries structural similarity to the analgesic drug, tramadol. The latter drug exerts its analgesic effect mainly through serotonin–norepinephrine reuptake inhibition (SNRI) [50], and to its analgesic effect mainly through serotonin–norepinephrine reuptake inhibition (SNRI) [50], and to a minor extent, through blocking of the mu-receptor. The O-Demethylation of both venlafaxine and a minor extent, through blocking of the mu-receptor. The O-Demethylation of both venlafaxine tramadol resulted in active metabolites that were developed into drugs of their own rights. The fact and tramadol resulted in active metabolites that were developed into drugs of their own rights. that neither venlafaxine nor desvenlafaxine has analgesic effects, and that neither tramadol nor OThe fact that neither venlafaxine nor desvenlafaxine has analgesic effects, and that neither tramadol desmethyltramadol has antidepressant effects, emphasizes the close link between drug action and nor O-desmethyltramadol has antidepressant effects, emphasizes the close link between drug action drug structure. and drug structure. 5.1.3. Metabolic O-Dealkylation of Aralkoxy Groups Resulting in the Attenuation or Loss of Pharmacologic Activity: NSAIDs (Naproxen, Indomethacin, and Nabumetone) NSAIDs fall into five chemical classes: arylalkanoic acids, salicylates, fenamates, oxicams (cyclic sulfonamides), and diarylheteroaromatics. The benzene ring, either as a separate entity or fused with
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5.1.3. Metabolic O-Dealkylation of Aralkoxy Groups Resulting in the Attenuation or Loss of Pharmacologic Activity: NSAIDs (Naproxen, Indomethacin, and Nabumetone) NSAIDs fall into five chemical classes: arylalkanoic acids, salicylates, fenamates, oxicams (cyclic sulfonamides), and diarylheteroaromatics. The benzene ring, either as a separate entity or fused with other rings, constitutes an integral part of the pharmacophore in all the NSAID chemical classes. The carboxyl group (in the form of a carboxylate ion, COO− ) forms the other part of the pharmacophore in the arylalkanoic acid NSAIDs. With the exception of aspirin, the mechanism of action of the NSAIDs involves the competitive inhibition of arachidonic acid, the precursor of prostaglandins, from accessing the COX active cavity. The binding of the arylalkanoic acid NSAID to the amino-acid moieties in the COX active cavity involves ion–ion, ion–dipole, and hydrogen bonding through the carboxylate group (COO− ) and hydrophobic interactions through alkyl and aryl groups [51–54]. The alkyl groups are those of the methoxy and propionic acid moieties. Naproxen, indomethacin, and nabumetone (Figures 14–16, respectively) are NSAIDs that act through COX1/COX2 inhibition. They are about the only three arylalkanoic acid NSAIDs that Molecules 2018, 23, x FOR PEER REVIEW 11 of 29 Molecules 2018, 23, x FOR PEER REVIEW of 29 contain aromatic methoxy groups. Furthermore, nabumetone is a prodrug NSAID, which 11must Molecules 2018, 23, x FOR PEER REVIEW 11 of 29 first be activated the metabolic oxidation the carbonyl to the carboxy derivative, activated by the by metabolic oxidation of theofcarbonyl groupgroup to the carboxy derivative, 6activated by the metabolic oxidation ofFigure the carbonyl group to the carboxy derivative, 66-methoxynaphthylacetic acid, as shown in 16. methoxynaphthylacetic acid, asoxidation shown in Figure activated by the metabolic of the 16. carbonyl group to the carboxy derivative, 6methoxynaphthylacetic acid, as shown in Figure 16. methoxynaphthylacetic acid, as shown in Figure 16. CH3 CH3 OH CH * 3 OH CYP3A4 CYP3A4 * O OH CYP1A2 CYP3A4 CH3O * O CYP1A2 O CH3O CYP1A2 CH3O S-(+)-Naproxen
S-(+)-Naproxen S-(+)-Naproxen
H 3CO H 3CO H 3CO
CH3 CH3 OH *CH3 OH UGT2B7 * O OH UGT2B7 UGT2B7 * O O
S-O 6-Desmethylnaproxen S-O diglucuronide 6-Desmethylnaproxen S-O 6diglucuronide -Desmethylnaproxen (inactive) diglucuronide (inactive) (inactive)
HO HO S-O 6-Desmethylnaproxen HO
S-O 6-Desmethylnaproxen (inactive) S-O 6-Desmethylnaproxen (inactive) (inactive) of naproxen [55] Figure 14. Metabolic pathway
Figure Figure 14. 14. Metabolic Metabolic pathway pathway of of naproxen naproxen [55] [55] Figure 14. Metabolic pathway of naproxen [55]
N N O N O O
COOH HO COOH HO CH3COOH HO CYP2C9 CH3 CH3 CYP2C9
CYP2C9 Cl
N N O N O O
COOH COOH CH3COOH UGT2B7 CH3 UGT2B7 CH3 UGT2B7
(inactive) (inactive)
Cl Cl Cl O-Desmethylindomethacin
Cl Indomethacin Cl Indomethacin Indomethacin
Indomethacin Indomethacin diglucuronide Indomethacin diglucuronide conjugate diglucuronide conjugate (inactive) conjugate
O-Desmethylindomethacin
(50 % , major metabolite, inactive) O-Desmethylindomethacin (50 % , major metabolite, inactive) (50pathway % , major of metabolite, inactive)[56]. Figure 15. Metabolic indomethacin
Figure 15. Metabolic pathway of indomethacin [56]. Figure 15. 15. Metabolic Metabolic pathway pathway of of indomethacin indomethacin [56]. [56]. Figure
CY C CY P1YP P1 A21A A2 2
H3CO H3CO H3CO
O O O CH3 CH3 CH3
Nabumetone Nabumetone (prodrug) Nabumetone (prodrug) (prodrug)
OH OH CYP2D6 OH OH CYP2D6 O OH O OH H3CO HO CYP2D6 O O H3CO HO O O 6-Methoxynaphthylacetic acid H3CO HO 6-Hydroxynaphthylacetic acid
6-Methoxynaphthylacetic acid 6-Hydroxynaphthylacetic acid (inactive) (active metabolite) acid 6-Methoxynaphthylacetic 6-Hydroxynaphthylacetic acid (inactive) (active metabolite) (inactive) [57]. (active metabolite) Figure 16. Metabolic pathways of nabumetone
Figure 16. Metabolic pathways of nabumetone [57]. Figure Figure 16. 16. Metabolic Metabolic pathways pathways of of nabumetone nabumetone [57]. [57].
Stereochemistry of Arylalkanoic Acid NSAIDs Stereochemistry of Arylalkanoic Acid NSAIDs Stereochemistry of Arylalkanoic Acid NSAIDs in this section fall into two subclasses: arylpropionic The arylalkanoic acid NSAIDs presented The arylalkanoic acid NSAIDs presented in this section fall into two subclasses: arylpropionic acid NSAIDs, to whichacid belongs naproxen (Figure 14),section and arylacetic to which belong The arylalkanoic NSAIDs presented in this fall intoacid two NSAIDs, subclasses: arylpropionic acid NSAIDs, to which belongs naproxen (Figure 14), and arylacetic acid NSAIDs, to which belong indomethacin and 6-methoxynaphthylacetic acid, 14), the active metabolites nabumetone (Figures 15 acid NSAIDs, to which belongs naproxen (Figure and arylacetic acidofNSAIDs, to which belong indomethacin and 6-methoxynaphthylacetic acid, the active metabolites of nabumetone (Figures 15 and 16, respectively). Naproxen contains a chiral at themetabolites α-carbon ofofthe propionic acid moiety indomethacin and 6-methoxynaphthylacetic acid,center the active nabumetone (Figures 15 and 16, respectively). Naproxen contains a chiral center at the α-carbon of the propionic acid moiety as indicated by an asterisk in Figure 14, and so do other members of the arylpropionic acid NSAIDs, and 16, respectively). Naproxen contains a chiral center at the α-carbon of the propionic acid moiety as indicated by an asterisk in Figure 14, and so do other members of the arylpropionic acid NSAIDs, such as ibuprofen ketoprofen. Accordingly, these drugs exist as pairs,acid R-(−) and Sas indicated by an and asterisk in Figure 14, and so do other members of enantiomeric the arylpropionic NSAIDs, such as ibuprofen and ketoprofen. Accordingly, these drugs exist as enantiomeric pairs, R-(−) and S-
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Stereochemistry of Arylalkanoic Acid NSAIDs The arylalkanoic acid NSAIDs presented in this section fall into two subclasses: arylpropionic acid NSAIDs, to which belongs naproxen (Figure 14), and arylacetic acid NSAIDs, to which belong indomethacin and 6-methoxynaphthylacetic acid, the active metabolites of nabumetone (Figures 15 and 16, respectively). Naproxen contains a chiral center at the α-carbon of the propionic acid moiety as indicated by an asterisk in Figure 14, and so do other members of the arylpropionic acid NSAIDs, such as ibuprofen and ketoprofen. Accordingly, these drugs exist as enantiomeric pairs, R-(−) and S-(+). The COX-inhibition activity of the arylpropionic acid NSAID subclass was found to reside in its S-(+)-enantiomers while the R-(−)-enantiomers were inactive [58]. However, the inactive R enantiomers in some members, such as naproxen and ibuprofen, are metabolically inverted unidirectionally to the active S-enantiomers, and hence, may be considered as prodrugs. Generally, when the metabolic functionalization of a chiral drug occurs at a distant group from the chiral center, the absolute configuration of the enantiomers of the parent drug may be extended to its metabolite. However, this ought not to be the case with optical activity, which is only determined experimentally. Of all the arylalkanoic acid NSAIDs, only S-naproxen and its sodium salt are internationally marketed as enantiopure drugs. In this context, S-(+)-ibuprofen and S-(+)-ketoprofen are marketed in some countries. All the other arylpropionic acid NSAIDs are marketed as racemates. When the racemate of an enantiopure drug was either previously used or is currently in circulation, the enantiopure drug is known as a chiral-switch drug. This definition applies to S-(+)-naproxen whose racemate use was stopped, and to S-(+)-ibuprofen and S-(+)-ketoprofen whose racemates are currently in circulation. S-Naproxen, indomethacin, and the active form of nabumetone are mainly metabolized through O-demethylation to give 6-O-desmethylnaproxen, O-desmethylindomethacin, and 6-hydroxynaphthylacetic acid, respectively (Figures 14–16). The first two O-desmethyl metabolites are devoid of COX inhibitory effects, and accordingly, of NSAID activity [59–61]. By analogy, 6-hydroxynaphthylacetic acid, the O-desmethyl metabolite of nabumetone [62], is expected to be devoid of NSAID activity. According to Duggan et al. (1972), the p-hydroxy groups in the O-desmethyl metabolites place polar, hydrogen-bond-donating properties within otherwise entirely aromatic, hydrophobic, pharmacophoric groups in the parent drugs [59]. Presumably, a poor metabolite–COX fit would result in subsequent loss of pharmacologic activity. The loss of pharmacologic activity in the O-desmethylarylalkanoic acid NSAIDs is further reflected upon in the discussion section. 5.2. Overall Discussion The phase I metabolic O-dealkylation of aralkoxy groups almost invariably occurs in all the drugs containing these moieties. From the cited drug examples in this section, the metabolic O-dealkylation of aralkoxy groups results in three situations regarding pharmacologic activity: (1) (2) (3)
Enhancement of activity is exhibited by the O-desmethyl morphinan opioids, O-desmethyltramadol and O-desethyl phenacetin; Retention of activity is exhibited by O-desmethyl venlafaxine; Significant attenuation or loss of activity is exhibited by O-desmethyl naproxen and O-desmethyl indomethacin.
Some inferences can be made from the effect on pharmacologic activity in the three NSAID cases upon considering the new state of structural affairs created by the loss of the hydrophobic aralkoxy-alky group and the generation of the hydrophilic hydroxy group. The effect mostly depends on the site of drug action involved. The cases where the activity is enhanced involve the opioid drugs acting on the mu-receptor. In these drugs, the aromatic ring A, an integral part of the pharmacophore (Figure 14), binds to the receptor through hydrophobic forces of attraction. The hydroxy group on the aromatic ring plays the logistic role of optimally anchoring the hydrophobic aromatic ring in its hydrophobic pocket in the mu receptor [24]. The same theory may be extended to the acetanilide/phenacetin/paracetamol
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case, where the sites of action are the H2 synthase enzymes used in the formation of prostaglandin, as was recently proposed [44]. The loss of pharmacologic activity upon O-demethylation of the aryl-methoxy group is mainly observed in the NSAIDs, naproxen and indomethacin, and is inferred for nabumetone. In this class of arylalkanoic acid NSAIDs, COX inhibition is due to hydrogen bonding and ion pairing due to the carboxyl group, and van der Waals contacts due to hydrophobic groups, mainly the aromatic rings. In addition, in the arylpropionic acid NSAIDs, the α-methyl group forms an essential hydrophobic interacting group. Furthermore, the methyl group in the methoxy moiety in naproxen, nabumetone, and indomethacin occupies a hydrophobic pocket in COX. Duggan et al. (2010) [59] reported that the methoxy group of naproxen is oriented toward the apex of the COX active site, and forms van der Waals interactions with Trp 387 and Tyr 385. The methoxy group in naproxen (as well as in nabumetone and indomethacin) is of special importance since its metabolic demethylation results in the polar, hydrogen-bonding hydroxyl group. According to Duggan et al. (2010) [59], the hydroxyl group in O-desmethylnaproxen places polar, hydrogen-bonding properties within an entirely hydrophobic pocket that was occupied by the methyl group of the methoxy moiety in naproxen, which is consistent with a reduction in COX inhibition. Furthermore, a pharmacokinetic effect is most probably involved in the attenuation of COX inhibition by the O-desmethyl metabolites of naproxen, 6-methoxynaphthylacetic acid, and indomethacin. In explanation, aromatic hydroxy groups are almost invariably metabolized Molecules 2018, 23, x FOR PEER REVIEW 13 of 29 in phase II to the highly water-soluble and rapidly eliminated glucuronide (and sometimes sulfate) conjugates. Such an effect will lead to a reduction in the effective concentration of the metabolite II to the highly water-soluble and rapidly eliminated glucuronide (and sometimes sulfate) conjugates. at theSuch receptor or will enzyme active cavity,inthus resulting in curtailing activity. to an effect lead to a reduction the effective concentration of or thelosing metabolite at theAccording receptor Fura or (2006), attenuation or loss of pharmacologic activity is associated with the biotransformation of enzyme active cavity, thus resulting in curtailing or losing activity. According to Fura (2006), pharmacophoric groups the possible accompanying changes in physicochemical properties attenuation or loss and of pharmacologic activity is associated with the biotransformation of [61]. pharmacophoric and the possible accompanying changesindicates in physicochemical properties [61]. The retention ofgroups antidepressant activity of desvenlafaxine a non-essential hydrophobic Theof retention of antidepressant activity of desvenlafaxine indicates a anon-essential hydrophobic binding role the methoxy methyl group in venlafaxine. Nevertheless, hydrogen-bonding role may binding role of the methoxy methyl group in venlafaxine. Nevertheless, a hydrogen-bonding role not be excluded since it is provided by the methoxy oxygen in venlafaxine and by the hydroxy group may not be excluded sincethis it isoccurs provided by the methoxy oxygen venlafaxine in desvenlafaxine; however, more prominently in thein latter drug. and by the hydroxy group in desvenlafaxine; however, this occurs more prominently in the latter drug.
5.3. Arenolic Metabolites Resulting from Aromatic Ring Hydroxylation 5.3. Arenolic Metabolites Resulting from Aromatic Ring Hydroxylation
The mechanism of metabolic aromatic-ring hydroxylation involves, as a first step, the formation The mechanism of metabolic aromatic-ring hydroxylation involves, as a first step, the formation of anofepoxide (arene oxide) intermediate, rapidly and spontaneously toarenol the arenol an epoxide (arene oxide) intermediate,which which rearranges rearranges rapidly and spontaneously to the product in most instances (Figure 17) product in most instances (Figure 17)[62,63]. [62,63]. R
R
R spontaneous rearrangement
[O] O
Arene
Arene oxide
OH
Arenol (a phenol)
Aromatic-ring hydroxylation catalyzed by a variety of enzymes in different xenobiotic molecules
Figure 17. Mechanism of aromatic-ring hydroxylation.
Figure 17. Mechanism of aromatic-ring hydroxylation.
Metabolic aromatic-ring hydroxylation assumes its importance from the fact that a large number
Metabolic aromatic-ring its importance fromorthe factwith thatother a large number of drug molecules contain hydroxylation the benzene ringassumes as a separate entity (phenyl) fused rings, alicyclic or heterocyclic. drug molecules, rings serve the(phenyl) dual role or of providing relatively of drug molecules contain In the benzene ringaromatic as a separate entity fused with other rings, largeorhydrophobic sites interaction with aromatic receptors or acting as carriers for role otherof functional groups. alicyclic heterocyclic. Infor drug molecules, rings serve the dual providing relatively However, not all of the benzene rings in drug molecules are subject to metabolic hydroxylation. This large hydrophobic sites for interaction with receptors or acting as carriers for other functional groups. is because certain electronic and steric effects dictate the metabolic hydroxylation of aromatic rings. However, not all of the benzene rings in drug molecules are subject to metabolic hydroxylation. This is These effects include the following, with possible anomalous events [64,65]: because certain electronic and steric effects dictate the metabolic hydroxylation of aromatic rings. The include least substituted aromatic ringpossible will be favorably oxidized, These(a)effects the following, with anomalous eventsespecially [64,65]: at the least hindered carbon atom; (b) The activated ring (i.e., the ring bearing an electron-donating group such as an alkyl) will be better oxidized; (c) Ring-deactivating groups (generally groups with negative inductive effects such as halo and nitro groups) discourage ring hydroxylation; (d) Being the farthest from steric effects in di-substituted benzene rings, the para position is the
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(a) (b) (c) (d) (e) (f)
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The least substituted aromatic ring will be favorably oxidized, especially at the least hindered carbon atom; The activated ring (i.e., the ring bearing an electron-donating group such as an alkyl) will be better oxidized; Ring-deactivating groups (generally groups with negative inductive effects such as halo and nitro groups) discourage ring hydroxylation; Being the farthest from steric effects in di-substituted benzene rings, the para position is the favored site of hydroxylation; If two aromatic rings in a drug molecule have the same chemical environment, hydroxylation will occur in only one of them; When the parent drug contains an aromatic hydroxy group, further metabolic hydroxylation is generally not favored even if there is more than one aromatic ring.
Aromatic-ring hydroxylation of drugs leads to the formation of inactive metabolites, metabolites with attenuated activity, and metabolites that are equiactive with the parent drugs. These situations are reviewed using selected representative drugs. The basis for the choice of the candidate drugs is as follows:
• Varying the chemical classes of the drugs; Varying the pharmacologic • Molecules 2018, 23, x FOR PEER REVIEW class of the drugs, and accordingly, the type of drug-site-of-action 14 of 29 interaction involved (i.e., the mechanism of action of the class of drugs); •• Varying the aromatic aromatic characteristics characteristics in in both both the the number number of of rings rings and and chemical chemical environment. environment. Varying the Metabolic aromatic-ringhydroxylation hydroxylation leading toloss theofloss of activity is exemplified by the Metabolic aromatic-ring leading to the activity is exemplified by the following: following: (a) The central nervous system depressant anticonvulsant drugs, phenobarbital and phenytoin, of (a) The central nervous system depressant anticonvulsant drugs, phenobarbital and phenytoin, of the imide chemical class (Figure 18); the imide chemical class (Figure 18); (b) The CNS depressant tranquilizer benzodiazepines, diazepam (Figure 19) and estazolam (b) The CNS depressant tranquilizer benzodiazepines, diazepam (Figure 19) and estazolam (Figure (Figure 20); 20); (c) The arylalkanoic acid NSAIDs, diclofenac, flurbiprofen, and ketorolac (Figures 21–23, (c) The arylalkanoic acid NSAIDs, diclofenac, flurbiprofen, and ketorolac (Figures 21–23, respectively), and the pyrazolone NSAID derivative, phenylbutazone (Figure 24); respectively), and the pyrazolone NSAID derivative, phenylbutazone (Figure 24); (d) The Theanticoagulant anticoagulantwarfarin warfarin (Figure (Figure 25). 25). (d) Metabolic aromatic-ring aromatic-ring hydroxylation hydroxylation leading leading to to attenuation attenuation of of activity activity is is exemplified exemplified by by the the Metabolic CNS depressant and major tranquilizer, chlorpromazine (Figure 26). CNS depressant and major tranquilizer, chlorpromazine (Figure 26). O
N 5
O
N
O
NH 1
5
CYP2C9
O
O NH 1
O
4'-Hydroxyphenobarbital (inactive)
HO
Phenobarbital
glucuronide or sulfate conjugation at the pheolic OH group
H N
O
H N
O CYP2C9
O
O N H
N H
OH
Phenytoin
5-(4-Hydroxyphenyl)5-phenyl-hysantoin (inactive)
Figure 18. Major metabolic pathways of phenobarbital and phenytoin. Figure 18. Major metabolic pathways of phenobarbital and phenytoin. CH3
* Cl
CH3
CH3 O
N N
3
OH
(major)
8
Cl 7
O
1 N
9
CYP3A4
B
A
3 N
6 6' 5'
1' C
(minor)
N
Cl 1'
2' 3'
O
N
4'
H OH
Phenytoin Phenytoin
OH
5-(4-Hydroxyphenyl)5-phenyl-hysantoin 5-(4-Hydroxyphenyl)5-phenyl-hysantoin (inactive) (inactive)
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Figure 18. Major metabolic pathways of phenobarbital and phenytoin. Figure 18. Major metabolic pathways of phenobarbital and phenytoin. CH3
N
CH3
CH3 O
CH N 3
O CH 1 N 3 O (major) 8 9 1 N B 3 (major) 8 A Cl 7 A B N 3 6 1' N Cl 7 2' 6 6' 1' C 2' 6' 5' C 3' 5' 4' 3' Diazepam 4'
O 3
Cl
* OH N* 3 OH
Cl
N
Temazepam (active) Temazepam (active)
O
CH N 3
9
CYP3A4
O
N
CYP3A4 (minor) (minor)
N
Cl 1'
Cl
N
1' 4' 4' OH
OH 4'-Hydroxydiazepam Diazepam 4'-Hydroxydiazepam (inactive) (inactive) The two hydroxy metabolites are further metabolized by glucuronide conjugation in phase II. The two hydroxy metabolites are further metabolized by glucuronide conjugation in phase II.
Figure 19. Metabolic pathways of diazepam. Figure Figure 19. 19. Metabolic Metabolic pathways pathways of of diazepam. diazepam. N
N NN N N 4 N * 4 OH N OH
Cl
CYP3A4 CYP3A4
(minor) (minor)
*
N
Cl
N
NN N N 4 N
(major) (major)
1' N 1' 2'
Cl
N
CYP3A4
N 4
Cl
N
CYP3A4 Cl
N
Cl
1"N 1"
4' 4'
3'2' 4'
4-Hydroxyestazolam 4-Hydroxyestazolam (inactive)
3'
OH
4'
Estazolam Estazolam
(inactive)
NN N
OH
4'-Hydroxyestazolam 4'-Hydroxyestazolam (inactive)
(inactive) The two hydroxy metabolites are further metabolized by glucuronide conjugation in phase II. The two hydroxy metabolites are further metabolized by glucuronide conjugation in phase II.
Figure 20. Metabolic pathways of estazolam. Figure 20. 20. Metabolic Metabolic pathways pathways of of estazolam. estazolam. Figure
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Cl Cl 3' 3' 4' 4'
H N H N
HO HO
CH2COOH CH2COOH
Cl Cl
Cl Cl
CY CY P2P2 C9C9
Cl Cl
CH2COOH H CH2COOH N 1 1' H 3 1' N 1 3 Diclofenac Cl Cl
4 3A4 YPP3A CY C
Cl Cl
HO HO
H N H N Cl Cl
Diclofenac
5 C 5 C Y YPP2C9 2C 9 CH2COOH CH2COOH
H N H N Cl Cl
4'-Hydroxydiclofenac 4'-Hydroxydiclofenac (20-30%) (20-30%)
15 of 29 15 of 29
HO 3' HO 3'
Cl Cl
CH2COOH CH2COOH
H N H N Cl Cl
5 5 OH OH
3'-Hydroxydiclofenac 3'-Hydroxydiclofenac
5-Hydroxydiclofenac 5-Hydroxydiclofenac CH2COOH CH2COOH
4',5-Dihydroxydiclofenac 4',5-Dihydroxydiclofenac OH OH
Figure 21. Metabolic pathways of diclofenac. Figure 21. 21. Metabolic Metabolic pathways pathways of of diclofenac. diclofenac. Figure O O
N N
Ketorolac Ketorolac
OH OH O O
O O
CYP2C9 CYP2C9
O O
N N
OH OH
CYP2B7 CYP2B7 Gluc-O Gluc-O
O O
HO HO
p-Hydroxyketorolac (10%) p-Hydroxyketorolac (10%) (inactive NSAID) (inactive NSAID)
N N
* *
O-Gluc O-Gluc O O
p-Hydroxyketorolac glucuronide p-Hydroxyketorolac glucuronide (inactive) (inactive)
Figure 22. Metabolic pathways of ketorolac. Figure Figure 22. 22. Metabolic Metabolic pathways pathways of of ketorolac. ketorolac. CH3 CH3 CHCO2H *CHCO2H
2' 2' 1' 1'
CH3 CH3 CHCO2H *CHCO2H
*
F F HO HO HO HO
*
CH3 CH3 CHCO2H *CHCO2H
*
4;Hydroxy4;Hydroxyflurbiprofen flurbiprofen (40-47%) (40-47%)
3',4'-Dihydroxy3',4'-Dihydroxyflurbiprofen flurbiprofen
inactiv inactiv e metabo e metab
3' 3'
CYC PY2 P2 C9C 9
HO HO
O O
N N
Ketorolac Ketorolac
OH OH
O O
O O
CYP2C9 CYP2C9 HO HO
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N N
OH OH
O O
O O
CYP2B7 CYP2B7 Gluc-O Gluc-O
p-Hydroxyketorolac (10%) p-Hydroxyketorolac (10%) (inactive NSAID) (inactive NSAID)
N N
* *
O O
O-Gluc O-Gluc
p-Hydroxyketorolac glucuronide p-Hydroxyketorolac glucuronide (inactive) (inactive)
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Figure 22. Metabolic pathways of ketorolac. Figure 22. Metabolic pathways of ketorolac. CH3 CH3 CHCO2H *CHCO2H
CH3 CH3 CHCO2H *CHCO2H
2' 2' 1' 1'
*
F F
*
F F HO HO HO HO
(40-47%) (40-47%)
CH3 CH3 CHCO2H *CHCO2H
catechol catechol
Flurbiprofen Flurbiprofen
4;Hydroxy4;Hydroxyflurbiprofen flurbiprofen
3',4'-Dihydroxy3',4'-Dihydroxyflurbiprofen flurbiprofen
*
F F
HO HO H3CO H3CO
(5%) (5%)
CH3 CH3 CHCO2H *CHCO2H
3'-Hydroxy-4'3'-Hydroxy-4'methoxyflurbiprofen methoxyflurbiprofen
*
F F
inactiv inactiv e metabo e metabo lites lites
3' 3'
CY CY P2 P2 C9 C9
HO HO
(20-30%) (20-30%)
Figure Figure 23. 23. Metabolic Metabolic pathways pathways of of flurbiprofen. flurbiprofen. Figure 23. Metabolic pathways of flurbiprofen.
g ri n ati-rilnagtion m o y ar marotix lation d arhoy roxy hy d N N
N N
O O
N N
HO HO
N N
* *
O O
O O
Oxyphenbutazone Oxyphenbutazone
om
hy * d eg hy roomxyega-1 O * dro laat-1 O xy ion l a ti Phenylbutazone on Phenylbutazone (developed into an anti-inflammatory (developed into an anti-inflammatory metabolite drug) metabolite drug)
N N
N N O O
O O
* *
* *
OH OH
gamma-Hydroxyphenylbutazone gamma-Hydroxyphenylbutazone (devoid of anti-inflammatory activity (devoid of anti-inflammatory but has urocosuric activity) activity but has urocosuric activity)
Figure 24. Metabolism of phenylbutazone. Figure Figure 24. 24. Metabolism Metabolism of of phenylbutazone. phenylbutazone. Molecules 2018, 23, x FOR PEER REVIEW
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CY
phenyl S-Warfarin
5
OH 9
4
6 7
8
O 3*
1 O 2 O
P2
r ajo (m u t e ) ro
benzopyran
(The S enantiomer is three- to five-fold as active as the R enantiomer.) * chiral center
O
*
4 3
7
O 1
HO
CH3
O
S-7-Hydroxywarfarin (inactive)
c ar re d b o n y uct l ase (m i n rou or te )
11 CH3 10 12
OH
5
C9
OH
OH
11
* O
* CH3
O
11-Hydroxywarfarin (active)
Figure 25. 25. Metabolic Metabolic pathways pathways of of warfarin. warfarin. Figure N
N N 7
Cl
1 3
S 5
Chlorpromazine
N
CYP2D6 HO 7
S 5
Cl
1
UGT2B7 3
7-Hydroxychlorpromazine glucuronide
7-Hydroxychlorpromazine (major metabolite, moderately active)
Figure 26. Metabolic pathways of chlorpromazine.
Metabolic aromatic-ring hydroxylation leading to the formation of equiactive products is
8
7
8
du nylse (em c rou inotarse (m te ) i n rou or te )
O 2 O
benzopyran benzopyran (The S enantiomer is three- to five-fold as active as the Risenantiomer.) (The S enantiomer three- to five-fold * chiral center as active as the R enantiomer.) * chiral center Molecules 2018, 23, 2119
OH OH 11
OH O
*
CH3
* 11 * O
* CH3
O O 11-Hydroxywarfarin 11-Hydroxywarfarin (active) (active)
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Figure 25. Metabolic pathways of warfarin. Figure 25. Metabolic pathways of warfarin. N
N N
N N N
7 7
Cl CYP2D6 Cl 3 CYP2D6
1
1 S 5
HO 7 HO 7
3
S
N N
5 Chlorpromazine Chlorpromazine
1 S 5
S 5
Cl
1
Cl 3
UGT2B7 UGT2B7
3
7-Hydroxychlorpromazine 7-Hydroxychlorpromazine (major metabolite, moderately active) (major metabolite, moderately active)
7-Hydroxychlorpromazine glucuronide 7-Hydroxychlorpromazine glucuronide
Figure 26. Metabolic pathways of chlorpromazine. Figure 26. Metabolic pathways of chlorpromazine. Figure 26. Metabolic pathways of chlorpromazine.
Metabolic aromatic-ring hydroxylation leading to the formation of equiactive products is Metabolicaromatic-ring aromatic-ring hydroxylation leading to the formation of equiactive products is Metabolic exemplified by the following:hydroxylation leading to the formation of equiactive products is exemplified by the following: exemplified by the following: (a) The beta-blocker, propranolol, of the chemical class, aryloxypropanolamine (Figure 27); (a) The The beta-blocker,propranolol, propranolol,ofofthe thechemical chemicalclass, class,aryloxypropanolamine aryloxypropanolamine(Figure (Figure 27); (a) (b) Thebeta-blocker, β-hydroxy β-methylglutaryl coenzyme A reductase inhibitor, atorvastatin (used27); in lowering (b) The The β-hydroxy β-methylglutaryl coenzyme A reductase inhibitor, atorvastatin (used inlowering lowering (b) β-hydroxy β-methylglutaryl coenzyme A reductase inhibitor, atorvastatin (used in blood cholesterol level; Figure 28). blood cholesterol level; Figure28). 28). blood cholesterol level; Figure Metabolic-ring hydroxylation leading to enhancement of activity is exemplified by acetanilide Metabolic-ring hydroxylation leading to enhancement enhancement Metabolic-ring hydroxylation leading to of activity is is exemplified exemplifiedby byacetanilide acetanilideto to paracetamol, which was already discussed in Section 5.1.1. toparacetamol, paracetamol,which whichwas wasalready alreadydiscussed discussedininSection Section5.1.1. 5.1.1.
Figure 27. Metabolic pathways of propranolol. Figure 27. pathways Figure 27.Metabolic Metabolic pathwaysofofpropranolol. propranolol. Molecules 2018, 23, x FOR PEER REVIEW
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HO
*
Dihydroxyheptanoic acid moiety
(statin pharmacophore) F
3
* 5
F
A
H N
1
HO
COOH
*
OH
NH O
H
HO
CYP3A4
N
3R,5S-o-Hydroxyatorvastatin
C B
NH O
COOH OH
*
HO
*
D
3R,5S-A torvastatin (marketed enantiomer)
F
COOH
*
OH H
N
NH
OH
O
3R,5S-p-Hydroxyatorvastatin
Figure 28. Metabolism of atorvastatin. Figure 28. Metabolism of atorvastatin.
5.3.1. Metabolic Aromatic-Ring Hydroxylation Leading to Loss of Activity Phenobarbital/Phenytoin The anticonvulsant drug, phenobarbital (Figure 18), was chosen as a representative of the
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5.3.1. Metabolic Aromatic-Ring Hydroxylation Leading to Loss of Activity Phenobarbital/Phenytoin The anticonvulsant drug, phenobarbital (Figure 18), was chosen as a representative of the barbiturate group of drugs because it is the only member that contains an aromatic benzene ring susceptible to metabolic hydroxylation. On the other hand, the anticonvulsant drug, phenytoin (Figure 18), was selected for its similarity to phenobarbital with respect to chemical structure, pharmacologic activity, and even mechanism of action. Phenytoin additionally contains two benzene rings with an identical chemical environment. Both phenobarbital and phenytoin are metabolized by aromatic-ring hydroxylation (Figure 18), a process that led to a loss of pharmacologic activity [64–67]. The CNS depressant activity of barbiturates (sedative, hypnotic, and anticonvulsant) and its termination are mainly dependent on the drug lipophilicity, which is imparted by the aromatic rings and the alkyl groups [68]. Lipophilicity helps the barbiturates to cross the blood–brain barrier, exert their effects, and again facilitate their distribution to other tissues, thus reducing their effective concentrations at the brain’s gamma-aminobutyric acid receptors (GABA receptors). This redistribution process of the barbiturates is considered a deactivation process. In addition, metabolism plays a role in the deactivation of barbiturates. All barbiturates contain two alkyl groups at carbon 5 of the barbituric acid ring (Figure 18) with the exception of phenobarbital, which contains an alkyl group (ethyl) and a phenyl group. All the alkyl groups in barbiturates are metabolized by oxidation in phase I at the ω or ω-1 carbons to either primary or secondary alcohols, respectively. The primary alcoholic groups may further be oxidized to carboxyl (COOH) groups. On the other hand, the phenyl group in phenobarbital is metabolically oxidized to a phenolic group at the favored para position (Figure 18). All such hydrophilic functionalities are detrimental to the essential hydrophobicity of the alkyl and phenyl groups, and thus, to the ability of the resulting metabolites to cross the blood–brain barrier. Enhancement of the water solubility of the barbiturate metabolites and their subsequent, fast elimination is a further cause of termination of pharmacologic activity resulting from the introduction of hydrophilic functionalities. Even more, the phase I metabolites, either carboxylic or phenolic, may further be conjugated in phase II to glucuronides and/or sulfates (Figure 18) with a consequent further increase in water solubility, elimination, and termination of activity due to a reduction in the effective concentration at the receptor. Despite the fact that the pharmacokinetics of the barbiturates play a major role in their deactivation, a pharmacodynamic dimension cannot be excluded: the introduction of a hydrogen-bonding functionality, such as the hydroxy (OH) group, on an essentially hydrophobic site will most probably negatively affect binding to the GABAA receptor, resulting in a loss of pharmacologic activity. Furthermore, by replacing a hydrogen atom in the benzene ring, the hydroxyl group will create a steric effect and increase the metabolite molecule size, factors that are detrimental to the proper metabolite–receptor interactions, and thus, to a loss of pharmacologic activity. The two aromatic rings in phenytoin have identical chemical environments, and only one of them is hydroxylated, which is consistent with the rules of metabolic aromatic-ring hydroxylation. The same reasoning that applies to the loss of activity of the phenolic metabolite of phenobarbital discussed above should apply to the loss of activity of the phenolic metabolite of phenytoin. Further reasoning is considered in the discussion section. Benzodiazepines: Diazepam and Estazolam The benzodiazepines are CNS depressants used as minor tranquilizers, sedatives, hypnotics, and anticonvulsants; in these respects, they largely supersede the barbiturates. Their mechanism of action involves binding to GABAA receptors [69–71]. The benzodiazepines are metabolized through several phase I oxidative reactions, with some followed by phase II conjugative reactions. The metabolic pathways of the two benzodiazepine representative members, diazepam [72,73] and estazolam [74,75], are shown Figures 19 and 20, respectively, with only aromatic-ring hydroxylation discussed in this section. The other metabolic pathways of diazepam and estazolam are discussed where relevant.
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Due to favorable electronic and steric structural environments, diazepam and estazolam are about the only two members of the clinically used benzodiazepines to undergo metabolic aromatic-ring hydroxylation at the 40 position (Figures 19 and 20). In most of the other members, metabolic 40 -hydroxylation is possibly disfavored by the presence of an electron-withdrawing halo group at position 20 (fluoro in flurazepam, flunitrazepam, and quazepam, and chloro in triazolam and clonazepam; for the numbering of the benzodiazepine ring system, reference should be made to the structure of diazepam in Figure 19). The 4’-hydroxylation of both diazepam [72,73] and estazolam [74,75] resulted in inactive metabolites. Foye (2013) attributed the loss of sedative, hypnotic effects of 4’-hydroxyestazolam to two factors [71]. The first factor is of a pharmacodynamic nature. It is explained by the 4’-hydroxy group weakening optimal binding of the aromatic ring to the GABAA receptor via a steric effect: the hydroxyl group is substantially bulkier than the hydrogen atom. The expected result is, therefore, decreased receptor affinity and drug potency. The second factor is of a pharmacokinetic disposition, and results from decreased hydrophobicity (i.e., increased hydrophilicity), which results in the decrease of the effective concentrations of the circulating 40 -hydroxy metabolites due to enhanced polarity, water solubility, and elimination, as per se and as glucuronide conjugates. In the absence of reports regarding the loss of activity of 4’-hydroxydiazepam, an analogy may be extrapolated from that of 40 -hydroxyestazolam. In contrast to 4’ hydroxylation, metabolic hydroxylation at position 3 of the diazepine ring in diazepam (Figure 19) does not affected activity; rather, it introduces a pharmacokinetic dimension: the 3-hydroxy metabolite is more hydrophilic and is subject to glucuronide conjugation with subsequent enhanced rate of elimination, and hence, a shorter duration of action than diazepam. These observations tend to consolidate a major pharmacodynamic role of the 4’-aromatic-ring hydroxyl group on causing loss of activity of diazepam, as well as of estazolam. The plausible explanation is that the introduction of the hydrogen-bonding group (the hydroxy) into an essentially pharmacophoric hydrophobic moiety (the benzene ring) is detrimental to the optimal GABAA receptor binding. A halo group at position 2’ of the benzodiazepine backbone (ring C, Figure 19) serves three purposes: it adds a welcomed hydrophobicity to the drug, disfavors metabolic ring hydroxylation, and imparts a conformation-locking effect on the aromatic ring through a steric effect. The consequence of these effects could be enhanced selectivity on drug–receptor interaction, leading to higher efficacy and possibly higher potency. Increased hydrophobicity would tend to enhance blood–brain barrier penetration, and therefore, increased access to the GABAA receptor. In the above context, it would be worthwhile to investigate the effect of another halo group at position 6’ (Figure 19) on the conformation locking of the aromatic rings in analogy with the NSAID pair, fenoprofen/diclofenac. In diclofenac (Figure 21), the two ortho-positioned chloro groups resulted in a restricted conformation with consequent enhanced selectivity, efficacy, and potency compared to fenoprofen, in which the two chloro groups are absent [76]. With respect to stereochemistry, both diazepam and estazolam are achiral. However, metabolic hydroxylation at C3 of diazepam and C4 of estazolam (Figures 19 and 20, respectively) results in chiral metabolites. The significance of such chirality as related to metabolite activity is discussed in Part 2 of this review series, which deals with metabolic aliphatic-ring hydroxylation. NSAIDs The chemical classes of NSAIDs were discussed in Section 5.1.3. (1)
Diclofenac
Diclofenac is a phenylacetic acid NSAID. It was developed as a variant of fenoprofen by introducing two ortho-positioned chloro groups in the anilino-aromatic ring to restrict its free rotation [76]. This restriction of rotation increases selectivity, and hence, potency with respect to fenoprofen. The metabolism of diclofenac shown in Figure 21 [77] represents one of the anomalies of
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aromatic-ring hydroxylation in that hydroxylation occurs at the meta position of two chloro groups. The hydroxy metabolites are pharmacologically inactive. In accounting for the structure–activity relationship of diclofenac, Foye (2013) [78] proposed that the function of the two ortho chloro groups was to force the anilino-phenyl ring out of the plane of the phenylacetic acid portion. Such twisting, as proposed by Foye (2013) [78], is important in the binding of diclofenac to the active site of COX. The introduction of a hydroxy group in the anilino-phenyl group would create a hydrogen-bonding characteristic, which would weaken or hinder the necessary twisting, thus resulting in an attenuation or loss of pharmacologic activity. (2)
Ketorolac
Ketorolac (Figure 22) is a pyrrole-acetic acid derivative structurally related to indomethacin and tolmetin. It is metabolized to p-hydroxyketorolac (Figure 22), which is inactive. Both the carboxy and phenolic hydroxy groups are further metabolized via glucuronide conjugation to give pharmacologically inactive products [79,80]. In analogy to the previously discussed cases, the loss of activity of 4-hydroxy ketorolac may be attributed to both pharmacodynamic and pharmacokinetic effects. Pharmacodynamic effects are elaborated upon in the discussion section. Ketorolac contains a chiral center as designated by the asterisk in Figure 22. Its enantiomers differ in their pharmacodynamic effect: while the S-enantiomer acts as both a COX1/COX2 inhibitor and an analgesic, the R-enantiomer only retains the analgesic activity [80]. The stereochemical basis of the loss of activity caused by metabolic aromatic-ring hydroxylation of ketorolac is not known. (3)
Flurbiprofen
Flurbiprofen is an arylpropionic acid COX1/COX2-inhibitor NSAID. It is mainly metabolized by aromatic-ring hydroxylation, as shown in Figure 23, with loss of activity [81]. The metabolism of flurbiprofen shows a rather interesting pattern in that a catechol ring is formed in which the 40 -position is anomalously methylated to yield a methoxy group with reduced polarity. This metabolic route is reminiscent of that of adrenaline, which is metabolized by the methylation of the para-hydroxy group by the enzyme catechol-O-methyl transferase (COMT) [82]. Furthermore, the metabolic double hydroxylation of flurbiprofen to yield 3’,4’-dihydroxy flurbiprofen is also an anomaly of metabolic-ring hydroxylation. We recall metabolic aromatic-ring dihydroxylation in the same molecule is generally disfavored [65,66]. Similar to naproxen, flurbiprofen interacts with the COX active site through ion pairing involving the carboxylate group and van der Waals contacts involving the α-methyl and phenyl groups. The metabolically introduced hydroxyl groups on the aromatic ring will be detrimental to the hydrophobic-pocket fit, thus leading to a loss of activity. Other factors are considered in the discussion section. Being an arylpropionic acid derivative, flurbiprofen is a chiral drug as indicated by the asterisk in Figure 23. As for all members of the arylpropionic acid NSAID subclass, the anti-inflammatory (COX-inhibiting) activity resides in S-(+)-flurbiprofen; R-(−)-flurbiprofen is expected to be the enantiomer with analgesic activity. Whether metabolic aromatic hydroxylation of flurbiprofen abolishes both anti-inflammatory and analgesic activities or exhibits selectivity is not known. Miscellaneous: Warfarin Warfarin (Figure 25) is an anticoagulant drug used as a prophylactic in preventing thrombus formation in patients who are at high risk of developing thromboembolic disease. Warfarin is chiral with the S-enantiomer having three- to five-fold the activity of the R-enantiomer [83]. Warfarin contains two aromatic moieties, a benzopyran and a phenyl, in addition to a 2-butanone chain (Figure 25). The major metabolic pathway of warfarin is through the hydroxylation of the benzene ring of the benzopyran moiety, in addition to a minor route through the reduction of the side-chain keto group to a secondary alcohol (Figure 24) [84–87]. S-warfarin is metabolized by the CYP2C9 isoenzyme to S-7-hydroxywarfarin, while R-warfarin is metabolized by CYP1A2, CYP3A4, and CYP2C19 isoenzymes
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to R-6, R-7, R-8, and R-10 hydroxy warfarins [88]. The acidic hydroxy group at C4, being in conjugation with the benzene ring, possibly explains the preference of metabolic hydroxylation of the benzopyran ring over the phenyl group since it increases the electron density toward hydroxylation through a positive inductive effect. Furthermore, both warfarin enantiomers are metabolized through reduction of the side-chain keto group by carbonyl reductase to a secondary alcohol (Figure 25) [85–88]. It was observed that the hydroxy group introduced metabolically on the aromatic ring led to a loss of anticoagulant activity, while the hydroxy group resulting from side-chain keto reduction resulted only in attenuation of activity [85]. In addition, the metabolic reduction of the side-chain keto group in warfarin created a second chiral center. Such a state of affairs may impact on the pharmacodynamic and pharmacokinetic effects of the 11-hydroxywarfarin metabolite (Figure 25). Keto-group reduction and pharmacologic activity are the subject of alcoholic metabolites to be discussed in Part 2 of this review series. 5.3.2. Metabolic Aromatic-Ring Hydroxylation Resulting in Attenuation of Pharmacologic Activity Chlorpromazine Chlorpromazine (Figure 26) is a major tranquilizer used as an antipsychotic. It is metabolized in humans via two major routes [89–93]: (a) aromatic-ring hydroxylation at position 7 to a moderately active metabolite (Figure 26); and (b) sulfoxidation to an inactive metabolite. A minor deactivating route through N-demethylation also occurs. It should be noted that the metabolic hydroxylation of chlorpromazine is in accordance with the rule that groups with negative inductive effects, such as chloro, deactivating the ring to hydroxylation. 5.3.3. Aromatic-Ring Hydroxylation Resulting in Parent-Drug Equiactive Metabolites Propranolol Propranolol (Figure 27) is an aryloxypropanolamine β-adrenoceptor blocker used as an antihypertensive and antiangina agent. As shown in Figure 26, it is metabolized in humans to three major metabolites, two of which are inactive and one of which is as active as the parent drug. In naphthoyloxyacetic acid (metabolite I, Figure 27), the pharmacophore is ruptured, leading to a loss of activity. In metabolite II, glucuronide conjugation of the side-chain hydroxy group led to a loss of activity, while in 4-hydroxypropranolol (metabolite III), activity was maintained. Furthermore, 4-hydroxypropranolol is metabolized in phase II to the inactive glucuronide conjugate [94,95]. The metabolism of propranolol directs attention to two interesting points: (a) glucuronic-acid conjugation of both alcoholic and phenolic hydroxy groups leads to a loss of pharmacologic activity, a phenomenon that is true for most cases; and (b) alkoxy groups are aromatic-ring activators and para-directors in metabolic aromatic-ring hydroxylation. Propranolol is a monochiral drug as indicated by the asterisk in Figure 27. For all the monochiral aryloxypropanolamines, the β-adrenoceptor-blocking activity resides mainly in the S-(−)-enantiomer, with the R-(+)-enantiomer exhibiting minimal activity [96]. Despite this fact, however, all the clinically used aryloxypropanolamine β-adrenoceptor-blockers, except S-(−)-timolol, are used as racemates. When the metabolic change occurs at a group distant from the chiral center, as in 4-hydroxypropranolol, extrapolation of the absolute enantiomeric designation from the parent drug to the metabolite is possible. Accordingly, 4-hydroxypropranolol may be assigned the S designation. However, optical activity designation and pharmacological activity may not be extrapolated from the parent drug and are only subjects of experimental verification. Atorvastatin Atorvastatin (Figure 28) is an HMG-CoA reductase inhibitor used in lowering blood cholesterol and triglyceride levels. Atorvastatin is metabolized by CYP3A4 hydroxylation at the ortho- or
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para-position at ring D, as shown in Figure 28 [97,98]. Being electron withdrawing, both the fluoro group and the pyrrole ring (C) disfavor metabolic hydroxylation of rings A and B, respectively. Accordingly, in accordance with the rule, hydroxylation takes place at the least hindered benzene ring, i.e., ring D. The two metabolites are equiactive with the parent drug and account for about 70% of its overall circulating activity [97,98]. As designated by the asterisks in Figure 28, atorvastatin is a bichiral drug, and hence, exists in four enantiomeric forms: 3R5R, 3R5S, 3S5R, and 3S5S [99]. The marketed enantiomer is 3R5S [100]. The hydroxy metabolites of atorvastatin exist in the same enantiomeric forms as the parent drug. In explaining the equiactivity of the atorvastatin hydroxy metabolites, the molecule of atorvastatin can be dissected into two parts: the dihydroxyheptanoic acid moiety and the aromatic ring system with its substituents. Dr. Philip Portoghese (1988) [101], a medicinal chemist from the University of Minnesota, developed a concept called “message address,” which conceptually breaks a drug molecule up into two components: one, which “finds” the active site (the address), and the other, which actually delivers the drug’s chemical message. In atorvastatin, the dihydroxyheptanoic-acid moiety represents the message, while the aromatic-ring system with substituents represents the address. When the address is substantially large, a small-group metabolic change is not expected to result in a significant impact on its role. This is true for atorvastatin, which contains a four-ring system that mainly interacts with the active site of the enzyme via hydrophobic binding. Since the term “pharmacophore” is mostly used in the pharmacodynamics of drug action, we propose an adaptation of Dr. Portoghese’s concept by using the terms “primary pharmacophore” and “auxiliary (logistic) pharmacophore” as equivalent terms to “message” and “address”, respectively. By binding to the receptor, the auxiliary (logistic) pharmacophore will facilitate the anchoring of the primary pharmacophore in the proper orientation in the receptor or enzyme active cavity. The primary pharmacophore will then compete with the physiologic substrate for the binding sites in the receptor or enzyme active site. Phenylbutazone Two metabolites of phenylbutazone (Figure 24), which were isolated from human urine, possess some of the pharmacological activities of the parent drug. Metabolite I (oxyphenbutazone), formed by aromatic-ring hydroxylation, has the potent antirheumatic and sodium-retaining effects of phenylbutazone; it was developed into a drug of its own right. On the other hand, metabolite II, formed by the oxidation of the ω-1 carbon of the butyl side chain, also possesses reduced sodium-retaining properties, but it is a considerably more potent uricosuric agent than phenylbutazone [102,103]. Phenylbutazone binds to and deactivates prostaglandin H synthase and prostacyclin synthase through peroxide (H2 O2 )-mediated deactivation. The reduced production of prostaglandin leads to reduced inflammation in the surrounding tissues [103]. It is also pertinent to note that γ-hydroxyphenylbutazone, which results from ω-1 hydroxylation of the butyl side chain in phenylbutazone, is devoid of anti-inflammatory activity [104]. Metabolic, aliphatic hydroxylation and pharmacologic activity of the resulting metabolites is the subject of Part 2 of this review series. Despite phenylbutazone being a monochiral drug, the relationship between its stereochemistry and activity does not receive much interest, possibly because it was developed and used at a time when stereoselectivity of drug action was not a well-developed science. 5.4. Discussion of Metabolic Aromatic-Ring Hydroxylation For the drug cases reviewed in this section, except for diclofenac, the structural features, either electronic or steric, set above for the occurrence of aromatic-ring hydroxylation, conform well to the rule of thumb. Loss, decrease, or retention of pharmacologic activity upon aromatic-ring hydroxylation in the cited cases may reflect the status of the ring in the parent drug regarding its mechanism of interaction with the receptor. When hydrophobic binding of the aromatic ring with the receptor is essential for
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activity, introduction of the hydrophilic hydrogen-bonding hydroxy group will compromise the fit and will not be tolerated. The established hydrogen bonding may force the ring out of the plane of interaction with the receptor; the result will be loss of activity. The aromatic-ring dislodging is also assisted by a steric effect caused by the bulkier hydroxyl group in the metabolite relevant to the hydrogen atom in the parent drug. Furthermore, an increase in size and surface area of the metabolite caused by the hydroxyl group relevant to the parent drug may be synergistic factors in the poor fit of the aromatic ring in its hydrophobic pocket in the receptor. This was the case with phenobarbital and phenytoin (Figure 18), diazepam, (Figure 19), estazolam (Figure 20), NSAIDs (Figures 21–23), and warfarin (Figure 25). Furthermore, the phase II glucuronide conjugation of the aromatic hydroxy group is an important factor in causing loss of activity of the metabolite. It considerably enhances metabolite clearance, and accordingly, reduces its effective concentration at the receptor or enzyme active cavity. When aromatic-ring hydroxylation results in decreased activity, as in 7-hydroxychlorpromazine (Figure 26), three inferences present themselves as possible explanations of the observation: (a) the hydroxylated ring is auxiliary pharmacophoric; (b) the hydroxy group results in an increase in the optimal molecular size in the metabolite relative to the parent drug; (c) the hydroxy group weakens optimal binding of the aromatic ring to the receptor via a steric effect relevant to the hydrogen atom. In addition, a reduction in the effective concentration of the hydroxy metabolite at the receptor through glucuronide conjugation may play an important role. When the hydroxy metabolite is equiactive with the parent drug, two inferences can be tentatively made. Firstly, the hydroxylated aromatic ring is auxiliary, i.e., it plays the role of the address. This is the case with the statin drug, atorvastatin (Figure 28), where the three-aromatic-ring system is auxiliary pharmacophoric, and therefore, is not involved in essential binding to the enzyme [105]. However, the role of the three-aromatic-ring system is logistic, that of proper anchoring of the drug in the enzyme active cavity for optimal interaction of the primary pharmacophoric groups with the enzyme to take place. The second inference is associated with 4-hydroypropanolol (Figure 27), the equiactive metabolite of propranolol. Propranolol is a nonselective β1/β2-adrenoceptor blocker; it belongs to the aryloxypropanolamine chemical class. In this class of compounds, a hydrophilic amide substitution at position 4 of the aromatic ring imparts β1 antagonistic selectivity [106], such as in atenolol and practolol (Figure 29). On the other hand, a hydrophilic hydroxy substitution at the same position reverses the activity altogether, i.e., from antagonistic to agonistic, such as in prenalterol (Figure 29) [107]. It can, hence, be concluded that the nature of the hydrophilic group substitution at position 4 of the aryloxypropanolamines significantly dictates the pharmacologic outcome of the β1-receptor interaction. Based on the above facts, it may be inferred that 4-hydroxypropranolol is a tentative β1-adrenoceptor agonist pending experimental verification. Molecules 2018, 23, x FOR PEER REVIEW 23 of 29 6 O H2N
Hydrophilic amide group
5 4
OH 1 O
OH
H N
*
6 O
5
2 3
H3C
Atenolol
Hydrophilic amide group
(Selective beta-1adrenoceptor blocker) 6 5 HO 4
N 4 3 H
OH 1 O
*
1 O
*
H N
2
Practolol (Selective beta-1adrenoceptor blocker)
H N
2 3
Prenalterol (Beta-1-adrenoceptor agonist)
Figure and practolol. practolol. Figure 29. 29. Structures Structures of of atenolol atenolol and
The atorvastatin equiactive hydroxy metabolites furnish a useful inference: pharmacologic equiactivity of metabolites relative to the parent drug occurs when the metabolic functionalization takes place at the “address” or “auxiliary pharmacophore”. We will provide further examples of this phenomenon in Part 2 of this review series. Of the NSAIDs, phenylbutazone stands in a class of its own in that its mechanism of action does not involve the inhibition of COX, but rather the inhibition of prostaglandin H synthase. As shown
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The atorvastatin equiactive hydroxy metabolites furnish a useful inference: pharmacologic equiactivity of metabolites relative to the parent drug occurs when the metabolic functionalization takes place at the “address” or “auxiliary pharmacophore”. We will provide further examples of this phenomenon in Part 2 of this review series. Of the NSAIDs, phenylbutazone stands in a class of its own in that its mechanism of action does not involve the inhibition of COX, but rather the inhibition of prostaglandin H synthase. As shown in this section and in Section 5.1.3, a hydroxy group on the aromatic rings of arylalkanoic-acid COX1/COX2-inhibitor NSAIDs is detrimental to their pharmacologic activity. This is in contrast to phenylbutazone whose aromatic-hydroxy metabolite (oxyphenbutazone, Figure 24) is equiactive with the parent drug and was developed into an anti-inflammatory drug of its own right. The different mechanisms of action, and accordingly, the varying sites of drug action involved may explain the disparity between the activities of the hydroxyl metabolites of phenylbutazone and the arylalkanoic-acid NSAIDs. While pharmacodynamics may handsomely explain the pharmacological activity of drug hydroxy metabolites relative to the parent drugs, the role of the pharmacokinetics of these metabolites should not be excluded. In the cases where the pharmacologic activity of the hydroxy metabolite is either attenuated or lost relative to the parent drug, pharmacokinetic factors may come into perspective in two aspects. Firstly, the hydroxy metabolites are rapidly cleared by phase II conjugation, thus aiding in the termination of their action. Secondly, the hydroxy metabolites do not readily penetrate target tissues due to a reduction in membrane permeability caused by an increase in polar surface area, a limitation that affects their active concentrations at the target site [108]. 6. Racemic Drugs versus Enantiopure Drugs Of all the chiral drugs presented as examples in this review, only levorphanol, S-(+)-naproxen, and 3R5S-atorvastatin are used clinically in enantiopure forms; the rest of the drugs are used as racemates. The use of a chiral drug as a racemate does not necessarily imply that the constituent enantiomers are identical in their pharmacodynamic, pharmacokinetic, or toxicologic properties. Difficulties in preparing the pure enantiomers via the separation from racemates or via enantioselective synthesis may be prohibitive factors due to a lack of technology and/or high cost. In some instances, however, despite the feasibility of separating or synthesizing the eutomer of a chiral drug, big international pharmaceutical companies seem not to be interested in the practice and they keep to the racemates. Certainly, they have their undeclared reasons for this. Nonetheless, the differences between the pharmacologic properties of the enantiomers of a chiral drug may seem insignificant to warrant their costly separation from the racemates or stereoselective synthesis. S-(+)-naproxen represents an example of chiral-switch drugs. A chiral-switch drug may be defined as “an enantiopure drug whose racemate was once used or is currently used clinically. On the other hand, levorphanol and 3R5S-atorvastatin represent examples of what may be described as “from-onset enantiopure drugs”. Some scientists [109], though acknowledging the importance of enantiopure drugs in advancing pharmacotherapy, expressed their reservations on the production and use of chiral-switch drugs such as levocetirizine, esomeprazole, and escitalopram on the basis of the insignificant therapeutic advantages they present. To the list, we may add S-(+)-ibuprofen, (a chiral-switch drug marketed in some countries as dexibuprofen). The addition is made on the basis of the metabolic inversion of the inactive R-(−)-enantiomer to the active antipode, as well as the current marketing of the racemate by big international pharmaceutical companies. Glucuronide Conjugation: Prevalence and Effect on Pharmacologic Activity Glucuronide conjugation is the most common phase II metabolic process [110], though certain structural features control its occurrence. It occurs with almost all aromatic hydroxy (arenolic) groups, most carboxyl groups, unhindered alcoholic hydroxy groups, and a few amino and sulfhydryl groups. Because of its relatively big size, glucuronic acid may not have easy access to active hydrogen-containing groups that are awkwardly situated in a molecule, i.e., sterically hindered groups.
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For instance, tertiary alcoholic groups such as 14-hydroxy in oxycodone (Figure 5) and 10 -hydroxy in tramadol (Figure 6) are sterically hindered, and hence, are not susceptible to glucuronide conjugation. With the exception of codeine glucuronide and morphine-6-glucuronide, glucuronide conjugation led to a loss of activity in all the cases presented in this review. With three hydroxy moieties and a completely ionized carboxyl moiety at physiologic pH, the glucuronide group considerably increases metabolite hydrophilicity, water solubility, elimination, and termination of action. In the end, the termination of activity is a consequence of the reduction in the effective concentration of the glucuronide conjugate at the receptor. With this pharmacokinetic concept of loss of activity for most drug glucuronide conjugates, the door is open only to pharmacodynamic speculation to explain the activity of codeine glucuronide and morphine-6-glucuronide. 7. Conclusions The hydroxy group is the most common hydrophilic group produced by metabolic functionalization in drug molecules. Aromatic hydroxy groups result in one of two ways: the O-dealkylation of aralkoxy groups or the hydroxylation of the aromatic ring. The O-dealkylation of aralkoxy groups in drug molecules is an invariably predictable metabolic route. On the other hand, metabolic aromatic-ring hydroxylation is governed by electronic and steric factors prevailing in the ring. The pharmacologic activity of the resulting arenolic metabolites resulting from both processes depends on the site of drug action (i.e., the receptor), as well as on the pharmacophoric or auxophoric status of the aromatic ring to which the alkoxy or hydroxy group is bonded. In general terms, phase I metabolic functionalization may reveal the status of a group in a drug molecule, whether primary or auxiliary pharmacophoric or auxophoric. Moreover, if there is previous knowledge of the pharmacophoric or auxophoric statuses of the rings, then the effect of the metabolically formed hydroxy group on the activity of the metabolite may be predicted. In addition to pharmacodynamic effects, the attenuation or loss of activity of polar metabolites may be explained by pharmacokinetic effects, which, by enhancing elimination, lead to a reduction in metabolite effective concentration at the receptor. When more active or equiactive metabolites showed favorable pharmacodynamic and pharmacokinetic properties, they were developed into drugs of their own rights. Nevertheless, not all equiactive metabolites were developed into drugs of their own rights, and hence, may be classified as drug-action-extension forms. Since, for the chiral drugs presented in this review, metabolic functionalization occurred at sites distant from the chiral center, absolute enantiomer configuration (as R or S) may be extrapolated from the parent drug to the hydroxy metabolite. However, optical activity designations (dextro or levo), as well as pharmacological activity, are the subject of experimental verification. Funding: This research received no external funding. Conflicts of Interest: The authors declare no conflict of interest.
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