N-异恶唑基联苯磺酰胺作为有效的血管紧张素II和内皮素A受体双重拮抗剂的发现。
Discovery of N-isoxazolyl biphenylsulfonamides as potent dual angiotensin II and endothelin A receptor antagonists.
作者信息
Murugesan Natesan, Tellew John E, Gu Zhengxiang, Kunst Bridgette L, Fadnis Leena, Cornelius Lyndon A, Baska Rose Ann F, Yang Yifan, Beyer Sophie M, Monshizadegan Hossain, Dickinson Kenneth E, Panchal Balkrushna, Valentine Maria T, Chong Saeho, Morrison Richard A, Carlson Kenneth E, Powell James R, Moreland Suzanne, Barrish Joel C, Kowala Mark C, Macor John E
机构信息
Discovery Chemistry and Metabolic and Cardiovascular Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-5400, USA.
出版信息
J Med Chem. 2002 Aug 29;45(18):3829-35. doi: 10.1021/jm020138n.
The ET(A) 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(1) receptor antagonists, including irbesartan (3). Thus, it was hypothesized that merging the structural elements of 2 with those of the biphenyl AT(1) 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, BMS-248360) as a potent and orally active dual antagonist of both AT(1) and ET(A) receptors. Compound 15 represents a new approach to treating hypertension.
内皮素A（ET(A)）受体拮抗剂（2）（N-(3,4-二甲基-5-异恶唑基)-4'-(2-恶唑基)-[1,1'-联苯]-2-磺酰胺，BMS-193884）与包括厄贝沙坦（3）在内的大量血管紧张素II 1型（AT(1)）受体拮抗剂具有相同的联苯核心结构。因此，有人提出假设，将2的结构元素与联苯AT(1)拮抗剂（如厄贝沙坦）的结构元素合并，将产生一种对两种受体都具有双重活性的化合物。这一策略导致了（15）（4'-[(2-丁基-4-氧代-1,3-二氮杂螺[4.4]壬-1-烯-3-基)甲基]-N-(3,4-二甲基-5-异恶唑基)-2'-[(3,3-二甲基-2-氧代-1-吡咯烷基)甲基]-[1,1'-联苯]-2-磺酰胺，BMS-248360）的设计、合成与发现，它是一种强效且口服活性的AT(1)和ET(A)受体双重拮抗剂。化合物15代表了一种治疗高血压的新方法。
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