Abstract

Endothelin (ET) receptor antagonists are of great potential clinical interest for the treatment pathological conditions associated with vasospasm, such as subarachnoid hemorrhage (SAH). We developed for parenteral use a compound of a class of trifunctionalized heteroarylsulfonamide pyrimidines specially designed for high water solubility. Ro 61–1790 [5-methyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2–1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-ylamide] is a competitive ET antagonist with an affinity to ET_Areceptor in the subnanomolar range. It has a ∼1000-fold selectivity for the ET_Avs. the ET_B receptor as assessed on functional assays (e.g., ET-1-induced inositol-1,4,5-triphosphate release or ET-1-induced intracellular calcium mobilization). Ro 61–1790 also had a high functional potency for inhibiting contraction induced by ET-1 on isolated rat aorta (ET_A receptors; pA₂ = 9.5) or by sarafotoxin S6c on rat trachea (ET_B receptors; pA₂ = 6.4). In vivo, Ro 61–1790 inhibited the pressor effect of big ET-1 in pithed rats with an ID₅₀ value of 0.05 mg/kg. Intravenous bolus of Ro 61–1790 induced a long-lasting antihypertensive effect in deoxycorticosterone acetate salt rats instrumented with telemetry. In a double-hemorrhage canine model of SAH, Ro 61–1790 both prevented and reversed cerebral vasospasm in a dose-dependent manner. In an established cerebral vasospasm, 3 mg/kg Ro 61–1790 i.v. was half as efficacious as intrabasilar papaverine. Ro 61–1790 (20 mg/kg/day) totally prevented the occurrence of vasospasm. In summary, these data demonstrate that Ro 61–1790 is a potent and selective ET_Areceptor antagonist suitable for parenteral use and potentially useful for preventing delayed ischemic deficit in patients with SAH.