phcnirammc {4.113)




- <S) -

pheniramine (4.113)

2 - CjH^N


("J *


chlorpheniramine (4.114)

A ■ ClCtHj

2 - C5H^N


- (S) -

chlorpheniramine (4.114)

2 - CjH^N

A - CICcH^


(R) -

brompheniramine (4, US)

A - ftrCfiJH,

2 - CSH«N

- (S) -

brompheniramine (4.115)


4 - BrCiHi

S-enantiomers in the USA and it has been reported that the reduced dose of the single isomers compared to the racemate resulted in a corresponding reduction in the sedative effects of these agents.

Within the dimethylaminoethyloxy ether series of compounds, i.e. derivatives of diphenhydramine (4.116), substitution of one of the phenyl rings or replacement of one ring by a 2-substituted pyridine ring results in the introduction of a chiral centre. The 4-methyl substituted derivative of diphenhydramine shows stereoselectivity in action, the A-enantiomer (4.117) being ca 65 times more potent than its antipode using a guineapig ileum test system. The 2-pyridyl derivative, carbinoxamine (4.118), also shows stereoselectivity in action the 5-enantiomer being ca 30 times more potent than the A-isomer. Comparison of the structures of the more potent isomers of these two compounds

(4.116); diphenhydramine with the eutomers of the pheniramine series, e.g. chlorpheniramine (4.114), illustrates the significance of considering the three dimensional structure of a molecule rather than the configurational designation when comparing biological activity.

Methyl substitution at the benzylic carbon results in an additional series of active agents, e.g. clemastine (4.119). In this example the basic dimethylamino group has been replaced by a 2-substituted pyrrolidine ring resulting in the introduction of an additional chiral centre. The activities of all four stereoisomers have been examined and the major determinant of activity is the configuration at the benzylic carbon atom, the pA2 values using guinea-pig ileum being: R,R, 9.45; R,S, 9.40; S,S, 7.99 and S,R, 8.57. The structure of clemastine (4.119) represents the R,R-stereoisomer the R-configuration at the benzylic carbon corresponding topologically to the active isomers of the previous series, clemastine is marketed as the single R,R-stereoisomer.

(4.114); (S) ■ chlorpheniramine {R) - (4J17)

(4.1 IS); (J) - caibinaxamine (4.119); (R, fi) - c!etiiastine

4.6.5 Non-steroidal anti-inflammatory drugs

2-Arylpropionic acids

The 2-arylpropionic acids (2-APAs) of general structure (4.20) are an important group of non-steroidal anti-inflammatory drugs (NSAIDs). The majority of these agents are used as racemic mixtures even though their major pharmacological activity, inhibition of cyclooxygenase, resides in the enantiomers of the S-absolute configuration, the R-enantiomers being either inactive, or weakly active, in in vitro test systems (Table 4.6). At present naproxen (4.58), flunoxaprofen (4.120), ibuprofen (4.21), in Austria, and ketoprofen, in Spain, are marketed as the single S-enantiomers. The large differences observed in the in vitro activity of the enantiomers of these agents decrease markedly in in vivo test systems and in some cases, e.g fenoprofen (4.121) and ibuprofen, the enantiomers appear to be essentially equipotent (Table 4.6). This difference in enantiomeric activity in vivo and in vitro is in part due to the metabolic chiral inversion of the inactive R-enantiomers to their active S-antipodes in both animals and man. The pharmacological activity of these agents, when administered as racemates is therefore closely linked with the stereochemical aspects of their metabolism.

The mechanism of the chiral inversion reaction is thought to involve the formation of an acyl-coenzyme A thioester of the R-enantiomer of the 2-APAs. The enzyme mediating this reaction has not been fully characterised but is believed to be an acyl CoA synthetase of the type involved in the metabolism of endogenous fatty acids. Once formed the (R)-2-arylpropionyl-coenzyme A thioester (4.122) undergoes epimerisation of the 2-arylpropionyl moiety to yield a mixture of both possible epimeric acyl-CoA derivatives, which may then undergo hydrolysis to liberate both enantiomers of the 2-arylpropionate. The enzymology of this process is not well understood but chemical synthesis and biochemical investigations on both possible acyl-CoA thioesters have indicated that both stereoisomers undergo the epimerisation reaction. The stereoselective step in the pathway appears to be formation of the (R)-2-arylpropionyl-CoA thioester, the S-enantiomers of the substrates being unable to form the thioester.

An alternative pathway to the hydrolysis of the acyl-CoA thioesters is acyl transfer of the 2-arylpropionyl moiety to glycerol resulting in the formation of "hybrid" triglycerides, e.g. (4.123) and hence distribution of the drug into adipose tissue. The stereochemistry of the 2-arylpropionic acid moiety found in adipose tissue has been investigated in the rat

(4J8); ($) - naproxen (4*21); (5) - ibuprofen

following administration of both the individual enantiomers and racemic ibuprofen. Administration of both (R,S')- and (R)-ibuprofen resulted in the incorporation of the drug into triglycerides, the enantiomeric composition of the material being R>S in both cases. Total drug lipid levels, following administration of equal doses, were approximately twice as high following the administration of (R)-ibuprofen than the racemate, whereas following the administration of (S)-ibuprofen only trace quantities of the drug could be detected. In vitro studies using (R)- and (S)-fenoprofen (4.121) as substrates and rat hepatocyte and adipocyte preparations, indicated stereoselective incorporation of (R)-fenoprofen into triglycerides and also that (R)- but not (S)-fenoprofen inhibited endogenous triglyceride synthesis in viro.

The above investigations indicate that both the (R)- and (S)-2-arylpropionyl moiety may be transferred from the acyl-CoA thioesters to glycerol but that the incorporation of drug depends upon the presence of the R-enantiomer, as would be expected from the stereoselectivity of acyl-CoA formation. The toxicological significance of drug incorporation is not known but it has been suggested that the formation of hybrid triglycerides may result in the accumulation of these agents and possible toxicity due to their effects on normal lipid metabolism and membrane function.

Chiral inversion has been reported for a number of the 2-arylpropionic acids in both animals and man, the extent of the reaction appears to be both substrate and species dependent. Human pharmacokinetic studies have shown that ibuprofen, fenoprofen and

Table 4.6 Relative activity of the enantiomers of 2-arylpropionic acid NSAIDs in in vitro and in vivo test systems.

Compound In vitro Test In vivo Test

Ratio S/R Ratio S/R

Compound In vitro Test In vivo Test

Ratio S/R Ratio S/R

Table 4.6 Relative activity of the enantiomers of 2-arylpropionic acid NSAIDs in in vitro and in vivo test systems.





Acute adjuvant



induced arthritis





Carrageenin paw

oedema; UVE

Flurbiprofen 200





Antagonism of







Toxin induced

writhing; Pain








Carrageenin paw



Granuloma pouch


Toxin induced






Carrageenin paw





Antipyretic activity




IPGS, inhibition of prostaglandin synthesis; IPA, inhibition of platelet aggregation; UVE, ultraviolet induced erythema.

IPGS, inhibition of prostaglandin synthesis; IPA, inhibition of platelet aggregation; UVE, ultraviolet induced erythema.

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