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 ETAreceptor in the subnanomolar range. It has a ∼1000-fold selectivity for the ETAvs. 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 ETAreceptor antagonist suitable for parenteral use and potentially useful for preventing delayed ischemic deficit in patients with SAH.
Footnotes
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Send reprint requests to: Dr. S. Roux, F. Hoffmann-La Roche Ltd., Pharma Division, Preclinical Research, P.O. Box, CH-4070 Basel, Switzerland.
- Abbreviations:
- ET
- endothelin
- SAH
- subarachnoid hemorrhage
- CHO
- Chinese hamster ovary
- COS
- African green monkey kidney
- BSA
- bovine serum albumin
- CSF
- cerebrospinal fluid
- DOCA
- deoxicorticosterone acetate
- HEK
- human embryonic kidney
- HPTLC
- high-performance thin-layer chromatography
- Ins(1
- 4,5)P3, inositol-1,4,5-trisphosphate
- i.v.
- intravenous
- Received April 10, 1997.
- Accepted August 5, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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