The Discovery of Sulfonamide Endothelin Antagonists and the Development of the Orally Active ETA Antagonist 5-(Dimethylamino)-N-(3,4-dimethyl-5- isoxazolyl)-1-naphthalenesulfonamide

Systemic hypertension induced by hepatic overexpression of human preproendothelin-1 in rats.

“…In several rat models of hypertension (SHR and DOCA-salt rats), there is no elevation in circulating ET-1 levels (11). However, endothelin receptor antagonists and antiendothelin antibodies have been reported to reduce blood pressure in a number of distinct rat models of hypertension, including SHR, DOCA-salt, reninoverexpressing transgenic TGR(mRen-2)27, and L-NAME treatment (15)(16)(17)(18)(42)(43)(44)(45)(46). The findings in the present study are complementary to these previous observations, indicating that in vivo overexpression of preproET-1 is sufficient to cause systemic hypertension under the conditions used in the present study.…”

“…A causal role for ET-1 in the pathophysiology of different diseases needs to be further delineated in humans. The availability of nonpeptide antagonists (15,17,57,58) will facilitate the establishment of pathophysiological roles of endogenous ET-1 in human patients.…”

“…SB 209670 administered alone is equally efficacious to the angiotensin II receptor blocker losartan in decreasing blood pressure in the TGR(mRen-2)27 hypertensive transgenic rats, and shows an additive hypotensive effect when administered together with losartan (16). Likewise, an orally active sulfonamide ET A antagonist decreases blood pressure by 25% in DOCA-salt rats (17). The ET A antagonist BQ-610 partially reverses the systemic and renal vasoconstrictor effects of nitric oxide synthetase inhibition (18).…”

Aspartate mutation distinguishes ETA but not ETB receptor subtype‐selective ligand binding while abolishing phospholipase C activation in both receptors

“…The ETA subtype binds ET-1, the cyclic pentapeptide antagonist BQ-123, and the naphthalenesulfonamide antagonist, BMS-182874, preferentially, whereas ET B binds ET-1, ET-3 and sarafotoxin $6c with approximately equal affinity [1][2][3][4]. Ro 46-2005 and Ro 47-0203 are pyrimidinyl naphthalenesulfonamide antagonists that bind both receptor subtypes with equal affinity [5,6].…”

Cardiovascular risk factors regulate the expression of vascular endothelin receptors

“…Modification of the sulfonamide derivative produced another potent ET A receptor 22 antagonist (Stein et al, 1994). Many endothelin receptor antagonists have since appeared, including some that are selective for ET A receptors, some that are selective for ET B receptors, and some that show similar affinities for both receptor subtypes.…”