FADROZOLE HYDROCHLORIDE - A POTENT, SELECTIVE, NONSTEROIDAL INHIBITOR OF AROMATASE FOR THE TREATMENT OF ESTROGEN-DEPENDENT DISEASE

被引：214

作者：

BROWNE, LJ

GUDE, C

RODRIGUEZ, H

STEELE, RE

BHATNAGER, A

机构：

[1] CIBA GEIGY CORP,DIV PHARMACEUT,RES DEPT,SUMMIT,NJ 07901

[2] CIBA GEIGY AG,DIV PHARMACEUT,RES DEPT,CH-4002 BASEL,SWITZERLAND

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1991年 / 34卷 / 02期

关键词：

D O I：

10.1021/jm00106a038

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A new class of potent, selective, nonsteroidal inhibitors of aromatase have been discovered. The most potent member of this series is fadrozole hydrochloride, CGS 16949 A, 4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzonitrile monohydrochloride, 26a. In addition, the 6,7-dihydropyrrolo[1,2-c]imidazole (21a) and the 6,7,8,9-tetrahydroimidazo[1,5-a]azepine (21b) analogues were synthesized and evaluated. CGS 16949 A's ability to selectively inhibit aromatase (IC50 = 4.5nM) over other cytochrome P-450 enzymes and suppress estrogen production when administered orally make it a suitable candidate to test the potential of an aromatase inhibitor in estrogen-dependent diseases including breast cancer.

引用

页码：725 / 736

页数：12

共 52 条

[1] MECHANISTIC STUDIES ON C-19 DEMETHYLATION IN ESTROGEN BIOSYNTHESIS [J].

AKHTAR, M ;

CALDER, MR ;

CORINA, DL ;

WRIGHT, JN .

BIOCHEMICAL JOURNAL, 1982, 201 (03) :569-580

[2]

AKHTAR M, 1986, BIOCHEM J, V109, P318

[3] STEREOSPECIFICITY OF OXIDATION AT C-19 IN ESTROGEN BIOSYNTHESIS [J].

ARIGONI, D ;

BATTAGLIA, R ;

AKHTAR, M ;

SMITH, T .

JOURNAL OF THE CHEMICAL SOCIETY-CHEMICAL COMMUNICATIONS, 1975, (06) :185-186

[4] INHIBITORS OF ESTROGEN BIOSYNTHESIS - PRECLINICAL STUDIES WITH CGS 16949A, A NEW NONSTEROIDAL AROMATASE INHIBITOR [J].

BHATNAGAR, AS ;

SCHIEWECK, K ;

HAUSLER, A ;

BROWNE, LJ ;

STEELE, RE .

PROCEEDINGS OF THE ROYAL SOCIETY OF EDINBURGH SECTION B-BIOLOGICAL SCIENCES, 1989, 95 :293-303

[5]

BOWMAN R M, 1988, Alphabet erocycic substituted tolunitriles, Patent No. [US4749713, 4749713]

[6]

BRODIE AMH, 1979, ENDOCRINOLOGY, V104, P118, DOI 10.1210/endo-104-1-118

[7] AROMATASE INHIBITION AND ITS PHARMACOLOGIC IMPLICATIONS [J].

BRODIE, AMH .

BIOCHEMICAL PHARMACOLOGY, 1985, 34 (18) :3213-3219

[8]

BRUGGEMEIER RW, 1978, J MED CHEM, V21, P1007

[9]

BRUGGEMEIER RW, 1982, STEROIDS, V40, P3065

[10]

BUTTERWORTH FC, 1940, J CHEM SOC, P355

← 1 2 3 4 5 6 →