Substrate interaction with 5 alpha-reductase enzyme: influence of the 17 beta-chain chirality in the mechanism of action of 4-azasteroid inhibitors

A series of steroidal compounds were synthesized in order to evaluate the p ossible influence of the configuration of a stereocenter in the 17 beta -si de chain on the inhibitory activity on the enzyme 5 alpha -reductase (5AR). For this purpose diastereomerically pure 4-azasteroids epimers at C-22 wer e prepared (compounds 1-11) and tested as inhibitors of 5AR in 'in vitro' t ests, The obtained data showed that in most cases the couples of epimers po ssess a significant difference in their biological activity. We also consid ered, for the tested molecules, a series of chemico-physical parameters in order to find a possible correlation with their biological activity. The fi ndings allowed us to propose a model of the binding site of 5AR which compr ises also, for 4-azasteroid inhibitors, the configurational aspect of the 1 7 beta -side chain. (C) 2001 Elsevier Science Inc. All rights reserved.