2. Academic Validation
  3. Biphenylsulfonamide endothelin antagonists: structure-activity relationships of a series of mono- and disubstituted analogues and pharmacology of the orally active endothelin antagonist 2'-amino-N- (3,4-dimethyl-5-isoxazolyl)-4'-(2-methylpropyl)[1, 1'-biphenyl]-2-sulfonamide (BMS-187308)

Biphenylsulfonamide endothelin antagonists: structure-activity relationships of a series of mono- and disubstituted analogues and pharmacology of the orally active endothelin antagonist 2'-amino-N- (3,4-dimethyl-5-isoxazolyl)-4'-(2-methylpropyl)[1, 1'-biphenyl]-2-sulfonamide (BMS-187308)

  • J Med Chem. 1998 Dec 17;41(26):5198-218. doi: 10.1021/jm970872k.
N Murugesan 1,  Z Gu,  P D Stein,  S Bisaha,  S Spergel,  R Girotra,  V G Lee,  J Lloyd,  R N Misra,  J Schmidt,  A Mathur,  L Stratton,  Y F Kelly,  E Bird,  T Waldron,  E C Liu,  R Zhang,  H Lee,  R Serafino,  B Abboa-Offei,  P Mathers,  M Giancarli,  A A Seymour,  M L Webb,  J T Hunt
Affiliations

Affiliation

  • 1 Departments of Chemistry, Cardiovascular Agents, Cardiovascular Biochemistry, and Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA. Murugesan@bms.com
PMID: 9857090 DOI: 10.1021/jm970872k
Abstract

Substitution at the ortho position of N-(3,4-dimethyl-5-isoxazolyl) benzenesulfonamide led to the identification of the biphenylsulfonamides as a novel series of endothelin-A (ETA) selective antagonists. Appropriate substitutions on the pendant phenyl ring led to improved binding as well as functional activity. A hydrophobic group such as isobutyl or isopropoxyl was found to be optimal at the 4'-position. Introduction of an amino group at the 2'-position also led to improved analogues. Combination of the optimal 4'-isobutyl substituent with the 2'-amino function afforded an analogue (20, BMS-187308) with improved ETA binding affinity and functional activity. Compound 20 also has good oral activity in inhibiting the pressor effect caused by an ET-1 infusion in rats. Doses of 10 and 30 micromol/kg iv 20 attenuated the pressor responses due to the administration of exogenous ET-1 to conscious monkeys, indicating that the compound inhibits the in vivo activity of endothelin-1 in nonhuman primates.

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