ENANTIOSELECTIVITY OF AROMATASE INHIBITORS - SUBSTITUTED 3-(4-AMINOPHENYL)PYRROLIDINE-2,5-DIONES

The (+)-, (-)-, and (+/-)-forms of 1- and 1,3-substituted 3-(4-aminoph enyl)pyrrolidine-2,5-dione have been examined as inhibitors of P450(AR OM) and P450(CSCC). The inhibitory potency for P450(AROM) resided in t he (+)-enantiomers of(1), (2), and (4) and the (-)-enantiomers of (3) and (5). These findings have been accommodated within a molecular grap hics-derived model for binding of P450(AROM) inhibitors to the substra te binding site, Crystallography showed that (+)-(2) has the (R)-confi guration. Spectral binding studies with human placental P450(AROM) sho wed type II binding but although the K-S values were in line with the IC50 values for individual compounds there was no overall correlation between K-S and IC50 within the series. There was little difference in the inhibitory potency of the enantiomers and racemate of individual compounds toward P450(CSCC). (C) 1995 Wiley-Liss, Inc.