STEROID 5-ALPHA-REDUCTASE - COMPARATIVE-STUDY OF MECHANISM OF INHIBITION BY NONSTEROIDS ONO-3805 AND LY191704

Two nonsteroids, ONO-3805 and LY191704, were evaluated as inhibitors o f the human and rat 5 alpha-reductases (5 alpha R). ONO-3805 was prepa red in a 12-step convergent synthesis. This compound is a potent inhib itor of the human and rat 5 alpha Rs, with more potent inhibition seen against the rat enzymes. The inhibition patterns of this compound wer e best fit to an uncompetitive model which suggests binding in a terna ry complex with enzyme and NADP(+). Apparent K-i values of 27, 31, 1, and 0.5 nM versus testosterone were obtained with human type 1, human type 2, rat type 1, and rat type 2 5 alpha R, respectively. Multiple i nhibition studies with ONO-3805 and NADP(+) support synergistic bindin g of these two inhibitors with all isozymes. LY191704 was also evaluat ed as an inhibitor of the human and rat 5 alpha Rs. This compound is a selective, competitive inhibitor of human type 1 5 alpha R. Poor inhi bition was observed with human type 2 and rat types 1 and 2 5 alpha R. (C) 1996 Academic Press, Inc.