Imidazole substituted biphenyls: A new class of highly potent and in vivo active inhibitors of P450 17 as potential therapeutics for treatment of prostate cancer

被引:64
作者
Wachall, BG [1 ]
Hector, M [1 ]
Zhuang, Y [1 ]
Hartmann, RW [1 ]
机构
[1] Univ Saarland, FR 12 1 Pharmaceut & Med Chem, D-66041 Saarbrucken, Germany
关键词
imidazole-substituted biphenyls; 17 alpha-hydroxylase-C17,20-lyase (P450 17); enzyme inhibitors; QSAR; theoretical calculations; antineoplastics;
D O I
10.1016/S0968-0896(99)00160-1
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
3- And 4-imidazol-1-yl-methyl substituted biphenyl compounds (named as meta- and para-substituted compounds) were synthesized bearing additional substituents in 3'-/4'-position as inhibitors of P450 17 (17 alpha-hydroxylase-C17,20-lyase). P450 17 is the key enzyme of androgen biosynthesis. Its inhibition is a novel therapeutic strategy for treatment of prostate cancer (PC). Twenty nine compounds were synthesized by Ar-Mg-Br, Negishi or Suzuki aryl-aryl cross coupling and tested toward human and rat enzyme. Most of the compounds showed moderate to excellent activity against one of the enzymes (0.087 mu M<IC(50)less than or equal to 7.7 mu M (ketoconazole: 0.74 mu M) for the human enzyme, 0.63 mu M less than or equal to IC(50)less than or equal to 32 mu M (ketoconazole: 67 mu M) for the rat enzyme). Interestingly, strong species differences were observed. In addition compounds were tested for inhibition toward P450 arom. The 3-imidazol-1-yl-methyl substituted compounds showed good inhibitory activity of P450 arom, while for the 4-substituted compounds negligible inhibition was found. For the most active group of P450 17 inhibitors, (i.e. the 4-imidazol-1-yl-methyl substituted compounds) a QSAR study was performed for inhibition of the human enzyme leading to the result that a hydrophilic substituent in 3'-/4'-position is very important. The most promising compounds (with respect to activity toward both enzymes) were tested in vivo using SD-rats for reduction of plasma testosterone concentrations 2 and 6 h after single ip application. The fluorine substituted compound Sc decreased the testosterone plasma concentration to castration level (after 2 h; 5 mg/kg) showing a biological half live of about 6h. (C) 1999 Elsevier Science Ltd. All rights reserved.
引用
收藏
页码:1913 / 1924
页数:12
相关论文
共 39 条
[1]  
Ahmed S, 1995, Drug Des Discov, V13, P27
[2]  
Ahmed S, 1994, Drug Des Discov, V12, P77
[3]  
Al-Hamrouni A. M., 1997, Pharmaceutical Sci, V3, P259
[5]   HYPOLIPIDEMIC IMIDAZOLES [J].
BAGGALEY, KH ;
HEALD, M ;
HINDLEY, RM ;
MORGAN, B ;
TEE, JL ;
GREEN, J .
JOURNAL OF MEDICINAL CHEMISTRY, 1975, 18 (08) :833-836
[6]   Inhibitors of cytochrome P450(17 alpha) (17 alpha-hydroxylase/C17,20 lyase) [J].
Barrie, SE ;
Jarman, M .
ENDOCRINE-RELATED CANCER, 1996, 3 (01) :25-39
[7]   Palladium catalyzed cross-coupling reaction of Grignard reagents with halobenzoic acids, halophenols and haloanilines [J].
Bumagin, NA ;
Luzikova, EV .
JOURNAL OF ORGANOMETALLIC CHEMISTRY, 1997, 532 (1-2) :271-273
[8]  
Burke DF, 1997, ANTI-CANCER DRUG DES, V12, P113
[9]   3- and 4-pyridylalkyl adamantanecarboxylates: Inhibitors of human cytochrome P450(17 alpha) (17 alpha-hydroxylase/C-17,C-20-lyase). Potential nonsteroidal agents for the treatment of prostatic cancer [J].
Chan, FCY ;
Potter, GA ;
Barrie, SE ;
Haynes, BP ;
Rowlands, MG ;
Houghton, J ;
Jarman, M .
JOURNAL OF MEDICINAL CHEMISTRY, 1996, 39 (17) :3319-3323
[10]  
CUBERES MR, 1985, SYNTHESIS-STUTTGART, P302