Rhizopus delemar lipase catalyzed ester hydrolysis of the alpha-methoxy-beta-phenylpropanoate (I) affords the (R)-(+) and (S)-(-) isomers in > 84% enantiomeric excess. Abs. stereochem. was detd. by a single crystal X-ray anal. of a related synthetic analog. 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 isomerization of the (R)-(+) isomer. Binding studies using recombinant human PPAR-gamma (peroxisomal proliferator activated receptor gamma), now established as a mol. target for this compd. class, indicate a 20-fold higher binding affinity for the (S) antipode relative to the (R) antipode.
|Number of pages||10|
|Journal||Bioorganic & Medicinal Chemistry|
|Publication status||Published - 1999|
Haigh, D., Allen, G., Birrell, H. C., Buckle, D. R., Cantello, B. C. C., Eggleston, D. S., Haltiwanger, R. C., Holder, J. C., Lister, C. A., Pinto, I. L., Rami, H. K., Sime, J. T., Smith, S. A., & Sweeney, J. D. (1999). Non-thiazolidinedione antihyperglycaemic agents. Part 3: The effects of stereochemistry on the potency of alpha-methoxy-beta-phenylpropanoic acids. Bioorganic & Medicinal Chemistry, 7(5), 821-830.