Indole and benzimidazole derivatives as steroid 5α-reductase inhibitors in the rat prostate

被引：19

作者：

Takami, H ^{[1
]}

Kishibayashi, N ^{[1
]}

Ishii, A ^{[1
]}

Kumazawa, T ^{[1
]}

机构：

[1] Kyowa Hakko Kogyo Co Ltd, Pharmaceut Res Inst, Shizuoka 4118731, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 1998年 / 6卷 / 12期

关键词：

enzyme inhibitors; substituent effects; 5; alpha-reductase; indole;

D O I：

10.1016/S0968-0896(98)80018-7

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A novel series of indole and benzimidazole derivatives were synthesized and evaluated for their inhibitory activity of rat prostatic 5 alpha-reductase. Among these compounds, 4-{2-[1-(4,4'-dipropylbenzhydryl)indole-5-carboxamido]phenoxy)butyric acid (15) and its benzimidazole analogue 25 showed potent inhibitory activities for rat prostatic 5 alpha-reductase (IC50 values of 9.6+/-1.0 and 13+/-1.5 nM, respectively), with the potency very close to that of finasteride. Compound 30, in which the moiety between the benzene ring and amide bond was replaced by quinolin-4-one ring, showed almost equipotent activity (IC50=19+/-6.2 nM) with the correspondent amide derivative 13. This result was consistent with the previous observation that the coplanarity of this moiety might contribute to the potent inhibitory activity. (C) 1998 Elsevier Science Ltd. All rights reserved.

引用

页码：2441 / 2448

页数：8

共 32 条

[1] A NONSTEROIDAL DIENE ACID INHIBITOR OF HUMAN TYPE-2 STEROID 5-ALPHA-REDUCTASE [J].

ABELL, AD ;

BRANDT, M ;

LEVY, MA ;

HOLT, DA .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1994, 4 (19) :2327-2330

[2] SYNTHESIS OF THE INDIVIDUAL ENANTIOMERS OF THE BENZOQUINOLINONE HUMAN TYPE-1 STEROID 5-ALPHA-REDUCTASE INHIBITORS LY191704 AND LY266111 [J].

AUDIA, JE ;

LAWHORN, DE ;

DEETER, JB .

TETRAHEDRON LETTERS, 1993, 34 (44) :7001-7004

[3]

BALD E, 1975, CHEM LETT, P61

[4] TREATMENT OF HIRSUTISM WITH 5-ALPHA-REDUCTASE INHIBITORS [J].

BROOKS, JR .

CLINICS IN ENDOCRINOLOGY AND METABOLISM, 1986, 15 (02) :391-405

[5] 5-ALPHA-REDUCTASE INHIBITORY AND ANTI-ANDROGENIC ACTIVITIES OF SOME 4-AZASTEROIDS IN THE RAT [J].

BROOKS, JR ;

BERMAN, C ;

PRIMKA, RL ;

REYNOLDS, GF ;

RASMUSSON, GH .

STEROIDS, 1986, 47 (01) :1-19

[6] HAIR-GROWTH EFFECTS OF ORAL-ADMINISTRATION OF FINASTERIDE, A STEROID 5-ALPHA-REDUCTASE INHIBITOR, ALONE AND IN COMBINATION WITH TOPICAL MINOXIDIL IN THE BALDING STUMPTAIL MACAQUE [J].

DIANI, AR ;

MULHOLLAND, MJ ;

SHULL, KL ;

KUBICEK, MF ;

JOHNSON, GA ;

SCHOSTAREZ, HJ ;

BRUNDEN, MN ;

BUHL, AE .

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 1992, 74 (02) :345-350

[7] 6-AZASTEROIDS - STRUCTURE-ACTIVITY-RELATIONSHIPS FOR INHIBITION OF TYPE-1 AND TYPE-2 HUMAN 5-ALPHA-REDUCTASE AND HUMAN ADRENAL 3-BETA-HYDROXY-DELTA(5)-STEROID DEHYDROGENASE 3-KETO-DELTA(5)-STEROID ISOMERASE [J].

FRYE, SV ;

HAFFNER, CD ;

MALONEY, PR ;

MOOK, RA ;

DORSEY, GF ;

HINER, RN ;

CRIBBS, CM ;

WHEELER, TN ;

RAY, JA ;

ANDREWS, RC ;

BATCHELOR, KW ;

BRAMSON, HN ;

STUART, JD ;

SCHWEIKER, SL ;

VANARNOLD, J ;

CROOM, S ;

BICKETT, DM ;

MOSS, ML ;

TIAN, GC ;

UNWALLA, RJ ;

LEE, FW ;

TIPPIN, TK ;

JAMES, MK ;

GRIZZLE, MK ;

LONG, JE ;

SCHUSTER, SV .

JOURNAL OF MEDICINAL CHEMISTRY, 1994, 37 (15) :2352-2360

[8]

GELLER J, 1989, PROSTATE, P95

[9] THE EFFECT OF FINASTERIDE IN MEN WITH BENIGN PROSTATIC HYPERPLASIA [J].

GORMLEY, GJ ;

STONER, E ;

BRUSKEWITZ, RC ;

IMPERATOMCGINLEY, J ;

WALSH, PC ;

MCCONNELL, JD ;

ANDRIOLE, GL ;

GELLER, J ;

BRACKEN, BR ;

TENOVER, JS ;

VAUGHAN, ED ;

PAPPAS, F ;

TAYLOR, A ;

BINKOWITZ, B ;

NG, J .

NEW ENGLAND JOURNAL OF MEDICINE, 1992, 327 (17) :1185-1191

[10] 19-nor-10-azasteroids: A novel class of inhibitors for human steroid 5 alpha-reductases 1 and 2 [J].

Guarna, A ;

Belle, C ;

Machetti, F ;

Occhiato, EG ;

Payne, AH ;

Cassiani, C ;

Comerci, A ;

Danza, G ;

DeBellis, A ;

Dini, S ;

Marrucci, A ;

Serio, M .

JOURNAL OF MEDICINAL CHEMISTRY, 1997, 40 (07) :1112-1129

← 1 2 3 4 →