Takami H, Koshimura H, Kishibayashi N, Ishii A, Nonaka H, Aoyama S, Kase H, Kumazawa T
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
J Med Chem. 1996 Dec 20;39(26):5047-52. doi: 10.1021/jm9601819.
A series of indole derivatives with varied substituents on the alpha, beta-unsaturated double bond were synthesized and evaluated for their ability to inhibit rat prostatic 5 alpha-reductase. Compounds possessing an ethyl substituent at the beta-position of the double bond showed potent inhibitory activity. Among them, (Z)-4-{2-[[3-[1-(4,4'-difluorobenzhydryl)indol-5-yl]-2-pentenoy l]- amino]phenoxy}butyric acid (16, KF20405) showed the maximum potency with an IC50 value of 0.48 +/- 0.086 nM, which was 20-fold higher potency than 1 (MK-906). Compound 16 effectively inhibited DHT production 4 h after a 3 mg/kg oral administration. Several potent indole derivatives, 1 and 2 ((+/-)-ONO-3805), were tested versus rat and human isozymes. Nonsteroidal inhibitors such as indole derivatives and 2 were 2-3 orders of magnitude less potent for human type 2 isozyme than steroidal inhibitor 1 and expressed a significant species deference for these isozymes.
合成了一系列在α,β-不饱和双键上带有不同取代基的吲哚衍生物，并评估了它们抑制大鼠前列腺5α-还原酶的能力。在双键的β位带有乙基取代基的化合物表现出强效的抑制活性。其中，(Z)-4-{2-[[3-[1-(4,4'-二氟二苯甲基)吲哚-5-基]-2-戊烯酰基]-氨基]苯氧基}丁酸（16，KF20405）表现出最大的效力，IC50值为0.48±0.086 nM，其效力比1（MK-906）高20倍。化合物16在口服3 mg/kg后4小时有效地抑制了双氢睾酮（DHT）的产生。测试了几种强效吲哚衍生物1和2（(±)-ONO-3805）对大鼠和人类同工酶的作用。与甾体抑制剂1相比，吲哚衍生物等非甾体抑制剂对人类2型同工酶的效力低2至3个数量级，并且对这些同工酶表现出明显的种属差异。
