Discovery of Ν-isoxazolyl biphenylsulfonamides as potent dual angiotensin II and endothelin A receptor antagonists

被引：47

作者：

Murugesan, N ^{[1
]}

Tellew, JE ^{[1
]}

Gu, ZX ^{[1
]}

Kunst, BL ^{[1
]}

Fadnis, L ^{[1
]}

Cornelius, LA ^{[1
]}

Baska, RAF ^{[1
]}

Yang, YF ^{[1
]}

Beyer, SM ^{[1
]}

Monshizadegan, H ^{[1
]}

Dickinson, KE ^{[1
]}

Panchal, B ^{[1
]}

Valentine, MT ^{[1
]}

Chong, SH ^{[1
]}

Morrison, RA ^{[1
]}

Carlson, KE ^{[1
]}

Powell, JR ^{[1
]}

Moreland, S ^{[1
]}

Barrish, JC ^{[1
]}

Kowala, MC ^{[1
]}

Macor, JE ^{[1
]}

机构：

[1] Bristol Myers Squibb Co, Pharmaceut Res Inst, Discovery Chem & Metab & Cardiovasc Drug Discover, Princeton, NJ 08543 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2002年 / 45卷 / 18期

关键词：

D O I：

10.1021/jm020138n

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The ETA receptor antagonist (2) (N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-[1,1'-biphenyl]-2-sulfonamide, BMS-193884) shares the same biphenyl core as a large number of AT, receptor antagonists, including irbesartan (3). Thus, it was hypothesized that merging the structural elements of 2 with those of the biphenyl AT, antagonists (e.g., irbesartan) would yield a compound with dual activity for both receptors. This strategy led to the design, synthesis, and discovery of (15) 4'- [(2-butyl-4-oxo-1,3-diazaspiro[4.4]non- 1-en-3-yl)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl-methyl]-[1,1'-biphenyl]-2-sulfonamide, BMS248360) as a potent and orally active dual antagonist of both AT, and ETA receptors. Compound 15 represents a new approach to treating hypertension.

引用

页码：3829 / 3835

页数：7

共 34 条

[1] CLONING AND EXPRESSION OF A CDNA-ENCODING AN ENDOTHELIN RECEPTOR [J].