New non-peptide endothelin-A receptor antagonists: Synthesis, biological properties, and structure-activity relationships of 5-(dimethylamino)-N-pyridyl-, -N-pyrimidinyl-, -N-pyridazinyl-, and -N-pyrazinyl-1-naphthalenesulfonamides

Use of automated synthesis led to the discovery of several 6-membered nitrogen heterocycles as replacements far the N-isoxazolyl substituent present in the 1-naphthalenesulfonamide endothelin-A (ET(A)) antagonist 5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide (BMS 182874). In each of these heterocycles, a small substituent such as halogen para to the position of attachment to the sulfonamide nitrogen atom was found to be advantageous for ET(A) receptor affinity. Of these heterocycles, 2-pyrazines offered the greatest scope for improving receptor affinity. Optimization of the substituents at the 3- and 5-positions in the pyrazine ring led to potent, ET(A)-selective compounds such as 5-(dimethylamino)-N-(5-chloro-3-methoxy-2 -pyrazinyl)-1-naphthalenesulfonamide (7m, ET(A) pIC(50) 8.1). When dosed orally at 10 mg/kg to conscious, normotensive rats infused with big ET-1, compounds such as 7m showed significant inhibition of the presser response with a duration of effect lasting for the 5-h course of the experiment.