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

Rhizopus delemar lipase catalysed ester hydrolysis of the alpha-methoxy-bet a-phenylpropanoate 1 affords the (R)-(+) and (S)-(-) isomers in >84% enanti omeric excess. Absolute stereochemistry was determined by a single crystal X-ray analysis of a related synthetic analogue. The activity of these two e nantiomers on glucose transport in vitro and as anti-diabetic agents in viv o is reported and their unexpected equivalence attributed to an enzyme-medi ated stereospecific isomerisation of the (R)-(+) isomer. Binding studies us ing recombinant human PPAR gamma (peroxisomal proliferator activated recept or gamma), now established as a molecular target for this compound class, i ndicate a 20-fold higher binding affinity for the (S) antipode relative to the (R) antipode. (C) 1999 Elsevier Science Ltd. All rights reserved.