Non-thiazolidinedione antihyperglycaemic agents. Part 3: The effects of stereochemistry on the potency of alpha-methoxy-beta-phenylpropanoic acids. |
| |
| Authors: | D Haigh G Allen H C Birrell D R Buckle B C Cantello D S Eggleston R C Haltiwanger J C Holder C A Lister I L Pinto H K Rami J T Sime S A Smith J D Sweeney |
| |
| Institution: | SmithKline Beecham Pharmaceuticals, New Frontiers Science Park North, Harlow, Essex, UK. david_haigh-1@sbphrd.com |
| |
| Abstract: | Rhizopus delemar lipase catalysed ester hydrolysis of the alpha-methoxy-beta-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 PPARgamma (peroxisomal proliferator activated receptor gamma), 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. |
| |
| Keywords: | |
|
|
