Steroid 5α-Reductase: Comparative Study of Mechanism of Inhibition by Nonsteroids ONO-3805 and LY191704

✍ Scribed by Georgianna S. Harris; Kenneth Ellsworth; Bruce E. Witzel; Richard L. Tolman

• Book ID: 102563866
• Publisher: Elsevier Science
• Year: 1996
• Tongue: English
• Weight: 235 KB
• Volume: 24
• Category: Article
• ISSN: 0045-2068
• DOI: 10.1006/bioo.1996.0033

✦ Synopsis

Two nonsteroids, ONO-3805 and LY191704, were evaluated as inhibitors of the human and rat 5Ͱ-reductases (5ͰR). ONO-3805 was prepared in a 12-step convergent synthesis. This compound is a potent inhibitor of the human and rat 5ͰRs, with more potent inhibition seen against the rat enzymes. The inhibition patterns of this compound were best fit to an uncompetitive model which suggests binding in a ternary complex with enzyme and NADP ϩ . 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 5ͰR, respectively. Multiple inhibition studies with ONO-3805 and NADP ϩ support synergistic binding of these two inhibitors with all isozymes. LY191704 was also evaluated as an inhibitor of the human and rat 5ͰRs. This compound is a selective, competitive inhibitor of human type 1 5ͰR. Poor inhibition was observed with human type 2 and rat types 1 and 2 5ͰR.