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 l ed to the development of 4-dimethyl-5-isoxazolyl)-1-naphthalenesulfona mides which were functional antagonists. Structural features which wer e important to activity included a 1,5-substitution pattern on the nap hthalene ring; a sulfonamide NH with a pK value < 7; an amine, prefera bly with alkyl substituents, at the 5-position; and methyl groups on b oth the 3- and 4-positions of the isoxazole.