Non-thiazolidinedione antihyperglycaemic agents. Part 3 : The effects of stereochemistry on the potency of α-methoxy-β-phenylpropanoic acids

Rhizopus delemar lipase catalysed ester hydrolysis of the α-methoxy-β-phenylpropanoate 1 affords the (R)-(+) and (S)-(−) isomers in >84% enantiomeric excess. Absolute stereochemistry was determined by a single crystal X-ray analysis of a related synthetic analogue. The activity of these two enantiomers on glucose transport in vitro and as anti-diabetic agents in vivo is reported and their unexpected equivalence attributed to an enzyme-mediated stereospecific isomerisation of the (R)-(+) isomer. Binding studies using recombinant human PPARγ (peroxisomal proliferator activated receptor γ), now established as a molecular target for this compound class, indicate a 20-fold higher binding affinity for the (S) antipode relative to the (R) antipode.