2. Academic Validation
  3. Biphenylsulfonamide endothelin receptor antagonists. 4. Discovery of N-[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]- 2-yl]methyl]-N,3,3-trimethylbutanamide (BMS-207940), a highly potent and orally active ET(A) selective antagonist

Biphenylsulfonamide endothelin receptor antagonists. 4. Discovery of N-[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]- 2-yl]methyl]-N,3,3-trimethylbutanamide (BMS-207940), a highly potent and orally active ET(A) selective antagonist

  • J Med Chem. 2003 Jan 2;46(1):125-37. doi: 10.1021/jm020289q.
Natesan Murugesan 1,  Zhengxiang Gu,  Steven Spergel,  Marian Young,  Ping Chen,  Arvind Mathur,  Leslie Leith,  Mark Hermsmeier,  Eddie C-K Liu,  Rongan Zhang,  Eileen Bird,  Tom Waldron,  Anthony Marino,  Barry Koplowitz,  W Griffith Humphreys,  Saeho Chong,  Richard A Morrison,  Maria L Webb,  Suzanne Moreland,  Nick Trippodo,  Joel C Barrish
Affiliations

Affiliation

  • 1 Department of Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-5400, USA. murugesan@bms.com
PMID: 12502366 DOI: 10.1021/jm020289q
Abstract

We have previously disclosed the selective ET(A) receptor antagonist N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide (1, BMS-193884) as a clinical development candidate. Additional SAR studies at the 2'-position of 1 led to the identification of several analogues with improved binding affinity as well as selectivity for the ET(A) receptor. Following the discovery that a 3-amino-isoxazole group displays significantly improved metabolic stability in comparison to its 5-regioisomer, the 3-amino-isoxazole group was combined with the optimal 2'-substituent leading to 16a (BMS-207940). Compound 16a is an extremely potent (ET(A) K(i) = 10 pM) and selective (80,000-fold for ET(A) vs ET(B)) antagonist. It is also 150-fold more potent and >6-fold more selective than 1. The bioavailability of 16a was 100% in rats and the systemic clearance and volume of distribution are higher than that of 1. In rats, intravenous 16a blocks big ET pressor responses with 30-fold greater potency than 1. After oral dosing at 3 micromol/kg, 16a displays enhanced duration relative to 1.

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