2. Chiral to chiral transformations
In transformations of this type metabolism takes place at a site in the molecule which does not alter the chirality of the metabolite relative to that of the drug.
Esmolol (4.76) is an ultra short acting, relatively cardioselective P-blocker, which is administered intravenously for the short term treatment of supraventricular arrhythmias and sinus tachycardia. The drug is used as a racemate but the pharmacological activity resides in the enantiomer of the S-configuration, the R-isomer being inactive as a P-blocker. The basis of the short duration of action, 10-15 min, is the rapid hydrolysis of the ester functionality by blood esterases. The hydrolysis of this agent shows considerable species variability, e.g. the hydrolysis of the S-enantiomer is faster than that of the R-isomer in the rhesus monkey, rabbit and guinea-pig and shows the reversed stereoselectivity in rat and dog. In man the hydrolysis of both enantiomers occur at similar rates.
Aromatic oxidation of warfarin (4.77) yields the 7-hydroxy metabolite, a reaction which is highly stereoselective for the more active S-enantiomer (ratio S:R:6:1) of the drug. In contrast oxidation at the 6 position of the coumarin ring system shows no stereoselectivity in man. In the rat 7-hydroxywarfarin is the major metabolite but for the R-enantiomer, i.e. the oxidation shows the reverse stereoselectivity compared to man. Recent studies using human DNA expressed cytochrome P450 isoenzymes have indicated that the isoform 2C9 is primarily responsible for the oxidation of (S)-warfarin to the 6- and 7-hydroxy compounds whereas isoform 1A2 is involved in the formation of R)-6-hydroxywarfarin. Warfarin also undergoes oxidation to yield the 4'- and 8-hydroxy derivatives each of which reactions shows a degree of stereoselectivity and it has been proposed that as a result of the regio (positional) and stereoselectivity of oxidation that warfarin could be used as a probe compound for the determination of the isoenzyme composition of hepatic cytochromes P450.
Transformations of this type involve the introduction of a second chiral centre into a chiral molecule. Such centres may arise by a Phase I metabolic transformation at a prochiral centre or by a Phase II metabolic transformation by reaction with a chiral conjugating agent.
Reactions of the first type include reduction of the prochiral ketone group in warfarin (4.77) to yield a pair of diastereoisomeric warfarin alcohols. In both rat and man the reduction is substrate selective for R)-warfarin (4.77) and the predominantly formed isomer of the alcohol (4.78) has the S-configuration at the new centre. The
Phase II or conjugation reactions of drug metabolism are synthetic and involve the combination of the drug, or a Phase I metabolite of the drug, with an endogenous molecule (see
Chapter 1). Many of the endogenous molecules involved in the conjugation reactions are chiral, e.g. D-glucuronic acid, the amino acid glutamine and the tripeptide glutathione, and hence chiral drugs which undergo conjugation with these agents will produce diastereoisomeric products.
Oxazepam (4.79) is a chiral benzodiazepine which is used as a racemic mixture. The individual enantiomers of oxazepam are stereochemically unstable and readily undergo racemisation in aqueous media and in contact with glass surfaces. Enantiomeric resolution is only possible when carried out under anhydrous conditions. Both enantiomers of oxazepam undergo conjugation with D-glucuronic acid to yield a pair of stereochemically stable diastereoisomeric conjugates the proportions of which vary between species. In man, dog and rabbit the diastereoisomer produced from (S)-oxazepam (4.80) predominates, S/R ratios varying between 2 to 3.4, whereas in the rhesus monkey (R)-oxazepam glucuronide (4.80) is preferentially formed (ratio S/R=0.5). The formation of the stereochemically stable glucuronides, and their direct analysis by high-performance liquid chromatography has facilitated the examination of the stereochemical aspects of disposition of the drug. It is of interest to note that hydrolysis of either diastereochemically pure conjugate results in the formation of the racemic drug.
Conjugation with the tripeptide glutathione (GSH; L-glutamyl-L-cysteinylglycine) involves reaction of the nucleophilic sulphur atom of the cysteine residue with electrophilic sites in foreign compounds. The reaction is mediated by the glutathione transferases, a family of isoenzymes with overlapping substrate specificity, found in the cytosolic and microsomal fractions of cells. The mechanism of conjugation with GSH appears to be
a single displacement substitution consistent with an SN2 type reaction and the substrate undergoes Walden inversion. As GSH contains two optically active amino acids in its structure if reaction occurs with a racemic substrate the glutathione conjugates are diastereoisomers. The conjugation of the obsolete chiral hypnotic agent bromoisovalerylurea (4.81) with GSH involves nucleophilic displacement of the bromine atom at the chiral centre and the glutathione conjugates (4.82) have the reverse configurational designation to those in the drug. In the case of a-bromoisovalerylurea the reaction is stereoselective for the R-enantiomer of the drug, the cytosolic enzyme(s) showing a three fold greater activity for the R compared to the S-enantiomer. The stereoselectivity of the reaction does vary with isoenzyme such that examination of purified enzyme systems indicates that the isoenzymes of the mu-family show a stereopreference for conjugation of R^-a-bromoisovalerylurea, whereas those of the alpha-family show a preference for the 5-enantiomer.
Transformations in which the chirality of a molecule is lost are relatively unusual. The best known examples involve the oxidation of secondary alcohols to yield the corresponding ketones but the investigation of such reactions is frequently complicated by the stereochemistry of the reverse reaction of reduction. The deamination of amphetamine (4.83) to yield the achiral phenylacetone (4.84) appears to be stereoselective for the A-enantiomer of amphetamine.
More recent examples of interest are provided by the 1,4-dihydropyridine calcium channel blocking agents, e.g. nilvadipine (4.85). These agents undergo P450 mediated oxidation to yield the corresponding achiral pyridine analogues (4.86). In the case of nilvadipine this reaction is stereoselective for the (+)-enantiomer in the rat, but for the (-)-enantiomer in dog and man.
Metabolic chiral inversion is a relatively rare transformation and involves the conversion of one enantiomer of a drug to its optical antipode with no other chemical change to the molecule. The reaction was initially observed with the 2-arylpropionic acid NSAIDs, e.g. ibuprofen (4.21) and has since been found to occur with the chemically related 2-aryloxypropionates, which are used as herbicides, e.g. haloxyfop (4.87). In the case of the 2-arylpropionic acids the reaction involves inversion of the relatively inactive
A-enantiomers to their active S-antipodes (4.20), whereas in the case of the 2-aryloxypropionates the reaction appears to be the reverse, i.e. the S-enantiomers are converted to their A-antipodes (4.37). This difference in the stereochemistry of the inversion reaction is apparent and arises as a result of the sequence rule designation, the three-dimensional spatial arrangement of the A-2-arylpropionic acids corresponding to that of an S-2-aryloxypropionate. The mechanism of this reaction will be examined in Section 4.7.5.
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