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

David Haigh, G. Allen, H.C. Birrell, D.R. Buckle, B.C.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

Research output: Contribution to journalArticlepeer-review

36 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)821-830
Number of pages10
JournalBioorganic & Medicinal Chemistry
Volume7(5)
Publication statusPublished - 1999

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