TY - JOUR T1 - Pharmacology of Tezosentan, New Endothelin Receptor Antagonist Designed for Parenteral Use JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 840 LP - 846 VL - 290 IS - 2 AU - Martine Clozel AU - Henri Ramuz AU - Jean-Paul Clozel AU - Volker Breu AU - Patrick Hess AU - Bernd-Michael Löffler AU - Philippe Coassolo AU - Sébastien Roux Y1 - 1999/08/01 UR - http://jpet.aspetjournals.org/content/290/2/840.abstract N2 - Tezosentan (Ro 61-0612) [5-isopropyl-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 new endothelin (ET) receptor antagonist specifically designed for parenteral use. Tezosentan competitively antagonizes the specific binding of 125I-labeled ET-1 and of the selective ETB receptor ligands 125I-labeled ET-3 and125I-labeled sarafotoxin S6c on cells and tissues carrying ETA and ETB receptors, with inhibitory constants in the nanomolar range, and has high water solubility. Tezosentan exhibits high functional inhibitory potency for inhibiting contraction induced by ET-1 on isolated rat aorta (ETAreceptors; pA2 = 9.5) and by sarafotoxin S6c on rat trachea (ETB receptors; pA2 = 7.7). In vivo, tezosentan inhibits the pressor effect of big ET-1 in pithed rats and increases ET-1 plasma concentrations in conscious rats in a dose-dependent fashion. In spontaneously hypertensive rats, i.v. injection of tezosentan has acute hemodynamic effects and decreases blood pressure. Tezosentan is also able to prevent the acute renal failure that complicates rhabdomyolysis in a rat model of myoglobinuric nephropathy. Finally, tezosentan exhibits an apparent elimination half-life of less than 1 h in rabbits and primates and of 2 h in rats. In conclusion, tezosentan, a potent mixed ET receptor antagonist with a short half-life, may offer a novel medical approach for the i.v. treatment of acute pathological conditions. The American Society for Pharmacology and Experimental Therapeutics ER -