Ethenesulfonamide derivatives, a novel class of orally active endothelin-Areceptor antagonists

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