Linking Aromatic Hydroxy Metabolic Functionalization of Drug Molecules to Structure and Pharmacologic Activity

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: arenolic drug metabolites; aromatic hydroxy metabolites; auxophores; metabolic O-dealkylation; metabolic aromatic-ring hydroxylation; metabolic modification of drug activity; primary and auxiliary pharmacophores.

Figure 1

Cytochrome P450 (CYP)-catalyzed O-dealkylation of alkyl or aralkyl ethers.

Figure 2

Chemical classification of methoxy-group-containing morphinan and non-morphinan opioids.

Figure 3

Metabolic pathways of codeine.

Figure 4

Metabolic pathways of hydrocodone.

Figure 5

Metabolic pathways of oxycodone.

Figure 6

Metabolic pathways of levomethorphan.

Figure 7

Metabolic pathways of tramadol.

Figure 8

Structures of the opioid drug pharmacophores.

Figure 9

Tramadol/O-desmethyltramadol and pethidine/ketobemidone.

Figure 10

Diamorphine, 6-acetylmorphine, and morphine.

Figure 11

Highly hydrophobic opioids.

Figure 12

From acetanilide to phenacetin to paracetamol.

Figure 13

Metabolic pathway of venlafaxine.

Figure 14

Metabolic pathway of naproxen [55]

Figure 15

Metabolic pathway of indomethacin [56].

Figure 16

Metabolic pathways of nabumetone [57].

Figure 17

Mechanism of aromatic-ring hydroxylation.

Figure 18

Major metabolic pathways of phenobarbital and phenytoin.

Figure 19

Metabolic pathways of diazepam.

Figure 20

Metabolic pathways of estazolam.

Figure 21

Metabolic pathways of diclofenac.

Figure 22

Metabolic pathways of ketorolac.

Figure 23

Metabolic pathways of flurbiprofen.

Figure 24

Metabolism of phenylbutazone.

Figure 25

Metabolic pathways of warfarin.

Figure 26

Metabolic pathways of chlorpromazine.

Figure 27

Metabolic pathways of propranolol.

Figure 28

Metabolism of atorvastatin.

Figure 29

Structures of atenolol and practolol.