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-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.
Haigh
D
D
SmithKline Beecham Pharmaceuticals, New Frontiers Science Park North, Harlow, Essex, UK. david_haigh-1@sbphrd.com
Allen
G
G
Birrell
H C
HC
Buckle
D R
DR
Cantello
B C
BC
Eggleston
D S
DS
Haltiwanger
R C
RC
Holder
J C
JC
Lister
C A
CA
Pinto
I L
IL
Rami
H K
HK
Sime
J T
JT
Smith
S A
SA
Sweeney
J D
JD
D000818:Animals; D018360:Crystallography, X-Ray; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D008956:Models, Chemical; D008958:Models, Molecular; D010666:Phenylpropionates / Q000138:chemical synthesis*; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D013237:Stereoisomerism; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism
D007004:Hypoglycemic Agents; D010666:Phenylpropionates; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors