Discovery and structure-activity relationships of sulfonamide ETA-selective antagonists.
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.
Stein
P D
PD
Department of Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.
Floyd
D M
DM
Bisaha
S
S
Dickey
J
J
Girotra
R N
RN
Gougoutas
J Z
JZ
Kozlowski
M
M
Lee
V G
VG
Liu
E C
EC
Malley
M F
MF
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
D065128:Endothelin Receptor Antagonists; D044022:Receptor, Endothelin A; D013449:Sulfonamides; D000096926:Benzenesulfonamides; C051353:naphthalenesulfonamide