2. Academic Validation
  3. Discovery of N-isoxazolyl biphenylsulfonamides as potent dual angiotensin II and endothelin A receptor antagonists

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

  • J Med Chem. 2002 Aug 29;45(18):3829-35. doi: 10.1021/jm020138n.
Natesan Murugesan 1,  John E Tellew,  Zhengxiang Gu,  Bridgette L Kunst,  Leena Fadnis,  Lyndon A Cornelius,  Rose Ann F Baska,  Yifan Yang,  Sophie M Beyer,  Hossain Monshizadegan,  Kenneth E Dickinson,  Balkrushna Panchal,  Maria T Valentine,  Saeho Chong,  Richard A Morrison,  Kenneth E Carlson,  James R Powell,  Suzanne Moreland,  Joel C Barrish,  Mark C Kowala,  John E Macor
Affiliations

Affiliation

  • 1 Discovery Chemistry and Metabolic and Cardiovascular Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-5400, USA. [email protected]
PMID: 12190306 DOI: 10.1021/jm020138n
Abstract

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.

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