Ethenesulfonamide Derivatives, a Novel Class of Orally Active Endothelin-A Receptor Antagonists

Abstract

In the present article we wish to report the discovery of a novel class of ET_A-selective endothelin (ET) receptor antagonists through the modification of the ET_A/ET_B non-selective antagonist, Ro47-0203 (Bosentan, 1). Replacement of the benzenesulfonamide group of 1 with a 2-phenylethenesulfonamide group gave compound 5a and resulted in improvement in ET_A-selectivity. Optimization of the alkoxy side chain attached to the core pyrimidine ring yielded the 2-fluoroethoxy derivative (5n) with further improvement of ET_A-selectivity. [IC₅₀=2.1 nM for ET_A receptor, ET_B/ET_A ratio=1200]. After oral administration, compound 5n inhibited the big ET-1 induced pressor response in pithed rats with a DR₂ value of 2.6 mg/kg and also exhibited a potent antagonistic activity in conscious rats.