Enantioselectivity of aromatase inhibitors: Substituted 3‐(4‐aminophenyl)pyrrolidine‐2,5‐diones

The (+)‐, (−)‐, and (±)‐forms of 1‐ and 1,3‐substituted 3‐(4‐aminophenyl)pyrrolidine‐2,5‐dione have been examined as inhibitors of P450 AROM and P450 CSCC . The inhibitory potency for P450 AROM resided in the (+)‐enantiomers of ( 1 ), ( 2 ), and ( 4 ) and the (−)‐enantiomers of ( 3 ) and ( 5 ). These findings have been accommodated within a molecular graphics‐derived model for binding of P450 AROM inhibitors to the substrate binding site. Crystallography showed that (+)‐( 2 ) has the (R)‐configuration. Spectral binding studies with human placental P450 AROM showed type II binding but although the K S values were in line with the IC 50 values for individual compounds there was no overall correlation between K S and IC 50 within the series. There was little difference in the inhibitory potency of the enantiomers and racemate of individual compounds toward P450 CSCC . © 1995 Wiley‐Liss, Inc.