Inhibitors of the P450 enzymes aromatase and lyase. Crystallographic and molecular modeling studies suggest structural features of pyridylacetic acid derivatives responsible for differences in enzyme inhibitory activity

Abstract

Derivatives of 4-pyridylacetic acid are known to be inhibitors of the cytochrome P450 enzymes aromatase and lyase (17 alpha-hydroxylase/C17-20lyase), and are therefore of interest in the treatment of hormone dependent breast and prostate cancers. We report the determination of the crystal structure of one such derivative, the 4-tert-butyl cyclohexyl ester, and molecular modeling studies on two related inhibitors, the cyclohexyl ester and its alpha-methyl derivative. These latter two compounds show a marked difference in their relative activities against aromatase and lyase. Two models are proposed for the interaction of these molecules with the target enzymes on the basis of their ability to adopt conformations that partially mimic steroid substrates. From these models an explanation can be advanced for the fact that, compared with the unmethylated analogue, the (racemic) alpha-methylated compound is seven times poorer as an inhibitor of aromatase but seven times better as an inhibitor of lyase. The model proposed for binding to aromatase places the alpha-carbon of the ester group in the position occupied by C(2) of steroid substrates. In contrast, that proposed for binding to lyase places this atom in the position occupied by C(17) of steroid substrates. The introduction of steric bulk at C(2) is known to be unfavorable for aromatase inhibition, while its introduction at C(17) may lead to a better mimicry of the steroid D-ring and so improve lyase inhibition.