Ro 61–1790, a New Hydrosoluble Endothelin Antagonist: General Pharmacology and Effects on Experimental Cerebral Vasospasm

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.