RO-61-1790, A NEW HYDROSOLUBLE ENDOTHELIN ANTAGONIST - GENERAL PHARMACOLOGY AND EFFECTS ON EXPERIMENTAL CEREBRAL VASOSPASM

Endothelin (ET) receptor antagonists are of great potential clinical i nterest for the treatment pathological conditions associated with vaso spasm, such as subarachnoid hemorrhage (SAH), We developed for parente ral use a compound of a class of trifunctionalized heteroarylsulfonami de pyrimidines specially designed for high water solubility, Ro 61-179 0 [5-methyl-pyridi ne-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methox y-phenoxy)-2-(2-1 H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-ylamide] i s a competitive ET antagonist with an affinity to ETA receptor in the subnanomolar range, it has a similar to 1000-fold selectivity for the ETA vs, the ETB receptor as assessed on functional assays (e.g., ET1-i nduced inositol-1,4,5-triphosphate release or ET-1-induced intracellul ar calcium mobilization). Po 61-1790 also had a high functional potenc y for inhibiting contraction induced by ET-I on isolated rat aorta (ET A receptors; pA(2) = 9.5) or by sarafotoxin S6c on rat trachea (ETB re ceptors; pA(2) = 6.4). in vivo, Ro 61-1790 inhibited the pressor effec t of big ET-1 in pithed rats with an ID50 value of 0.05 mg/kg. Intrave nous bolus of Ro 61-1790 induced a long-lasting antihypertensive effec t in deoxycorticosterone acetate salt rats instrumented with telemetry . In a double-hemorrhage canine model of SAH, Po 61-1790 both prevente d and reversed cerebral vasospasm in a dose-dependent manner, In an es tablished cerebral vasospasm, 3 mg/kg Po 61-1790 i.v. was half as effi cacious as intrabasilar papaverine. Ro 61-1790 (20 mg/kg/day) totally prevented the occurrence of vasospasm. in summary, these data demonstr ate that Ro 61-1790 is a potent and selective ETA receptor antagonist suitable for parenteral use and potentially useful for preventing dela yed ischemic deficit in patients with SAH.