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

3- And 4-imidazol-1-yl-methyl substituted biphenyl compounds (named as meta - and para-substituted compounds) were synthesized bearing additional subst ituents in 3'-/4'-position as inhibitors of P450 17 (17 alpha-hydroxylase-C 17,20-lyase). P450 17 is the key enzyme of androgen biosynthesis. Its inhib ition is a novel therapeutic strategy for treatment of prostate cancer (PC) . Twenty nine compounds were synthesized by Ar-Mg-Br, Negishi or Suzuki ary l-aryl cross coupling and tested toward human and rat enzyme. Most of the c ompounds 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) f or the human enzyme, 0.63 mu M less than or equal to IC(50)less than or equ al to 32 mu M (ketoconazole: 67 mu M) for the rat enzyme). Interestingly, s trong species differences were observed. In addition compounds were tested for inhibition toward P450 arom. The 3-imidazol-1-yl-methyl substituted com pounds showed good inhibitory activity of P450 arom, while for the 4-substi tuted compounds negligible inhibition was found. For the most active group of P450 17 inhibitors, (i.e. the 4-imidazol-1-yl-methyl substituted compoun ds) a QSAR study was performed for inhibition of the human enzyme leading t o the result that a hydrophilic substituent in 3'-/4'-position is very impo rtant. The most promising compounds (with respect to activity toward both e nzymes) were tested in vivo using SD-rats for reduction of plasma testoster one concentrations 2 and 6 h after single ip application. The fluorine subs tituted compound Sc decreased the testosterone plasma concentration to cast ration level (after 2 h; 5 mg/kg) showing a biological half live of about 6 h. (C) 1999 Elsevier Science Ltd. All rights reserved.