Biphenylsulfonamide endothelin receptor antagonists.: 2.: Discovery of 4′-oxazolyl biphenylsulfonamides as a new class of potent, highly selective ETA antagonists

被引:31
作者
Murugesan, N
Gu, ZX
Stein, PD
Spergel, S
Mathur, A
Leith, L
Liu, ECK
Zhang, RA
Bird, E
Waldron, T
Marino, A
Morrison, RA
Webb, ML
Moreland, S
Barrish, JC
机构
[1] Bristol Myers Squibb Pharmaceut Res Inst, Dept Chem, Princeton, NJ 08543 USA
[2] Bristol Myers Squibb Pharmaceut Res Inst, Dept Cardiovasc Agents, Princeton, NJ 08543 USA
[3] Bristol Myers Squibb Pharmaceut Res Inst, Dept Cardiovasc Biochem & Pharmacol, Princeton, NJ 08543 USA
[4] Bristol Myers Squibb Pharmaceut Res Inst, Dept Metab, Princeton, NJ 08543 USA
[5] Bristol Myers Squibb Pharmaceut Res Inst, Dept Pharmacokinet, Princeton, NJ 08543 USA
关键词
D O I
10.1021/jm000105c
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The synthesis and structure-activity relationship (SAR) studies of a series of 4'-oxazolyl-N-(3,4-dimethyl-5-isoxazolyl)[1,1'-biphenyl]-2-sulfonamide derivatives as endothelin-A (ETA) receptor antagonists are described. The data reveal a remarkable improvement in potency and metabolic stability when the 4'-position of the biphenylsulfonamide is substituted with an oxazole ring. Additional 2'-substitution of an acylaminomethyl group further increased the binding activity and provided one of the first subnanomolar ETA-selective antagonists in the biphenylsulfonamide series (17, ETA K-i = 0.2 nM). Among the compounds described, 3 (N(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide BMS-193884) had the optimum pharmacological profile and was therefore selected as a clinical candidate for studies in congestive heart failure.
引用
收藏
页码:3111 / 3117
页数:7
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