title: 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-+ ++pyri din-4-yl)-pyrimidin-4-ylamide] is a competitive ET antagonist with an affinity to ETA receptor in the subnanomolar range. It has a approximately 1000-fold selectivity for the ETA vs. the ETB 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 (ETA receptors; pA2 = 9.5) or by sarafotoxin S6c on rat trachea (ETB 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 ETA receptor antagonist suitable for parenteral use and potentially useful for preventing delayed ischemic deficit in patients with SAH.
authors.affiliation: F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Roux
authors.forename: V
authors.initials: V
authors.lastname: Breu
authors.forename: T
authors.initials: T
authors.lastname: Giller
authors.forename: W
authors.initials: W
authors.lastname: Neidhart
authors.forename: H
authors.initials: H
authors.lastname: Ramuz
authors.forename: P
authors.initials: P
authors.lastname: Coassolo
authors.forename: J P
authors.initials: JP
authors.lastname: Clozel
authors.forename: M
authors.initials: M
authors.lastname: Clozel
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004146:Dioxanes / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D006801:Humans; D002546:Ischemic Attack, Transient / Q000188:drug therapy*; D008297:Male; D011725:Pyridines; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011921:Rats, Inbred WKY; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D018411:Spodoptera; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy; D013449:Sulfonamides; D013777:Tetrazoles
chemical_list: D004146:Dioxanes; D065128:Endothelin Receptor Antagonists; D011725:Pyridines; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D013449:Sulfonamides; D013777:Tetrazoles; C109641:clazosentan