title: Discovery and structure-activity relationships of sulfonamide ETA-selective antagonists.
abstract: Random screening of compounds in an ETA receptor binding assay led to the discovery of a class of benzenesulfonamide ligands. Optimization led to the development of 5-amino-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamides which were functional antagonists. Structural features which were important to activity included a 1,5-substitution pattern on the naphthalene ring; a sulfonamide NH with a pK value < 7; an amine, preferably with alkyl substituents, at the 5-position; and methyl groups on both the 3- and 4-positions of the isoxazole.
authors.affiliation: Department of Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.
authors.forename: P D
authors.initials: PD
authors.lastname: Stein
authors.forename: D M
authors.initials: DM
authors.lastname: Floyd
authors.forename: S
authors.initials: S
authors.lastname: Bisaha
authors.forename: J
authors.initials: J
authors.lastname: Dickey
authors.forename: R N
authors.initials: RN
authors.lastname: Girotra
authors.forename: J Z
authors.initials: JZ
authors.lastname: Gougoutas
authors.forename: M
authors.initials: M
authors.lastname: Kozlowski
authors.forename: V G
authors.initials: VG
authors.lastname: Lee
authors.forename: E C
authors.initials: EC
authors.lastname: Liu
authors.forename: M F
authors.initials: MF
authors.lastname: Malley
mesh_terms: D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D065128:Endothelin Receptor Antagonists; D066298:In Vitro Techniques; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D044022:Receptor, Endothelin A; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000096926:Benzenesulfonamides
chemical_list: D065128:Endothelin Receptor Antagonists; D044022:Receptor, Endothelin A; D013449:Sulfonamides; D000096926:Benzenesulfonamides; C051353:naphthalenesulfonamide