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 compds. were synthesized in order to evaluate the possible influence of the configuration of a stereocenter in the 17beta-side chain on the inhibitory activity on the enzyme 5alpha-reductase (5AR). For this purpose diastereomerically pure 4-azasteroids epimers at C-22 were prepd. (compds. 1-11) and tested as inhibitors of 5AR in in vitro tests. The obtained data showed that in most cases the couples of epimers possess a significant difference in their biol. activity. We also considered, for the tested mols., a series of chemico-phys. parameters in order to find a possible correlation with their biol. activity. The findings allowed us to propose a model of the binding site of 5AR which comprises also, for 4-azasteroid inhibitors, the configurational aspect of the 17beta-side chain.