3-PHOSPHINIC ACID AND 3-PHOSPHONIC ACID STEROIDS AS INHIBITORS OF STEROID 5-ALPHA-REDUCTASE - SPECIES COMPARISON AND MECHANISTIC STUDIES

3-Phosphinic acid and 3-phosphonic acid steroids are presented as a new class of steroid 5α-reductase (SR) inhibitors. Representative compounds have been studied as inhibitors of prostatic SR from human, rat, and cynomolgus monkey (Macaca fascicularis). The most potent of the phosphinic acid inhibitors of the human enzyme activity demonstrated nanomolar inhibition constants, while the affinities of the phosphonic acids were diminished. Comparison of compound potency revealed interspecies variability with the best correlation on Ki Km for the two primate SRs. Results from dead-end and multiple inhibition analyses with 17β-(N,N-diisopropylcarbamoyl)androsta-3,5-diene-3-phosphinic acid (2a) and 17β-(N,N-diisopropylcarbamoyl)androsta-3,5-diene-3-phosphinic acid (3a) were consistent with the preferential binding of these compounds to an enzyme-NADP+ complex. The pH profiles of solubilized rat liver SR inhibition by 2a and 3a indicated preferential binding of the phosphinic and phosphonic acids as the anion and the monoanion, respectively. © 1991.