Hirosumi J, Nakayama O, Fagan T, Sawada K, Chida N, Inami M, Takahashi S, Kojo H, Notsu Y, Okuhara M
Exploratory Research Laboratories, Fujisawa Pharmaceutical Co. Ltd, Tsukuba Japan.
J Steroid Biochem Mol Biol. 1995 Apr;52(4):357-63. doi: 10.1016/0960-0760(94)00187-q.
Steroid 5 alpha-reductase is an enzyme which converts testosterone into 5 alpha-dihydrotestosterone (DHT) and is implicated in the pathogenesis of benign prostatic hyperplasia (BPH) in men. We studied in vitro effects of FK143, a nonsteroidal new compound, on 5 alpha-reductase in human and animal prostates. Prostates were obtained from Wistar rats, Beagle dogs, and Cynomolgus monkeys as well as prostatic tissue from BPH patients obtained by the prostatectomy. Nuclear membrane fraction of prostates showed pH dependent 5 alpha-reductase activities, and inhibitory effects of drugs were assayed at pH 6.5. FK143 inhibited human prostatic 5 alpha-reductase in a dose-dependent manner with an IC50 of 1.9 nM and also inhibited animal 5 alpha-reductases with similar IC50 values. FK143 inhibited human and rat 5 alpha-reductases in a noncompetitive fashion while finasteride, a steroidal 5 alpha-reductase inhibitor, showed competitive inhibition. The affinities of FK143 for the human 5 alpha-reductase is constant at pH 5 and 6.5. No inhibitory effects were shown to other oxidoreductases. These results indicate that FK143 is a new type of potent and selective 5 alpha-reductase inhibitor.
类固醇5α-还原酶是一种将睾酮转化为5α-双氢睾酮（DHT）的酶，与男性良性前列腺增生（BPH）的发病机制有关。我们研究了一种非甾体新化合物FK143对人和动物前列腺中5α-还原酶的体外作用。前列腺取自Wistar大鼠、比格犬和食蟹猴，以及通过前列腺切除术获得的BPH患者的前列腺组织。前列腺的核膜部分显示出pH依赖性的5α-还原酶活性，并在pH 6.5下测定药物的抑制作用。FK143以剂量依赖性方式抑制人前列腺5α-还原酶，IC50为1.9 nM，并且也以相似的IC50值抑制动物5α-还原酶。FK143以非竞争性方式抑制人和大鼠的5α-还原酶，而甾体5α-还原酶抑制剂非那雄胺则表现出竞争性抑制。FK143对人5α-还原酶的亲和力在pH 5和6.5时保持恒定。对其他氧化还原酶未显示抑制作用。这些结果表明FK143是一种新型的强效和选择性5α-还原酶抑制剂。
