title: Biphenylsulfonamide endothelin receptor antagonists. 2. Discovery of 4'-oxazolyl biphenylsulfonamides as a new class of potent, highly selective ET(A) antagonists.
abstract: The synthesis and structure-activity relationship (SAR) studies of a series of 4'-oxazolyl-N-(3,4-dimethyl-5-isoxazolyl)[1, 1'-biphenyl]-2-sulfonamide derivatives as endothelin-A (ET(A)) receptor antagonists are described. The data reveal a remarkable improvement in potency and metabolic stability when the 4'-position of the biphenylsulfonamide is substituted with an oxazole ring. Additional 2'-substitution of an acylaminomethyl group further increased the binding activity and provided one of the first subnanomolar ET(A)-selective antagonists in the biphenylsulfonamide series (17, ET(A) K(i) = 0.2 nM). Among the compounds described, 3 (N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1, 1'-biphenyl]-2-sulfonamide; BMS-193884) had the optimum pharmacological profile and was therefore selected as a clinical candidate for studies in congestive heart failure.
authors.affiliation: Department of Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-5400, USA. murugesan@bms.com
authors.forename: N
authors.initials: N
authors.lastname: Murugesan
authors.forename: Z
authors.initials: Z
authors.lastname: Gu
authors.forename: P D
authors.initials: PD
authors.lastname: Stein
authors.forename: S
authors.initials: S
authors.lastname: Spergel
authors.forename: A
authors.initials: A
authors.lastname: Mathur
authors.forename: L
authors.initials: L
authors.lastname: Leith
authors.forename: E C
authors.initials: EC
authors.lastname: Liu
authors.forename: R
authors.initials: R
authors.lastname: Zhang
authors.forename: E
authors.initials: E
authors.lastname: Bird
authors.forename: T
authors.initials: T
authors.lastname: Waldron
authors.forename: A
authors.initials: A
authors.lastname: Marino
authors.forename: R A
authors.initials: RA
authors.lastname: Morrison
authors.forename: M L
authors.initials: ML
authors.lastname: Webb
authors.forename: S
authors.initials: S
authors.lastname: Moreland
authors.forename: J C
authors.initials: JC
authors.lastname: Barrish
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D002339:Carotid Arteries / Q000187:drug effects / Q000502:physiology; D004353:Drug Evaluation, Preclinical; D065128:Endothelin Receptor Antagonists; D006973:Hypertension / Q000503:physiopathology; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D009119:Muscle Contraction; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D044022:Receptor, Endothelin A; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C412823:BMS 193884; D065128:Endothelin Receptor Antagonists; D010080:Oxazoles; D044022:Receptor, Endothelin A; D013449:Sulfonamides