Pharmacology of tezosentan, new endothelin receptor antagonist designed for parenteral use

Tezosentan (Ro 61-0612) [5-isopropyl-pyridine-2-sulfonic acid 6-(2-hydroxy- ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimid in-4-yl-pyrimidin-4-ylamide] is a new endothelin (ET) receptor antagonist s pecifically designed for pat-enteral use. Tezosentan competitively antagoni zes the specific binding of I-125-labeled ET-1 and of the selective ETB rec eptor ligands I-125-labeled ET-3 and I-125-labeled sarafotoxin S6c on cells and tissues carrying ETA and ETB receptors, with inhibitory constants in t he nanomolar range, and has high water solubility. Tezosentan exhibits high functional inhibitory potency for inhibiting contraction induced by ET-1 o n isolated rat aorta (ETA receptors; pA(2) = 9.5) and by sarafotoxin S6c on rat trachea (ETB receptors; pA(2) = 7.7). In vivo, tezosentan inhibits the pressor effect of big ET-1 in pithed rats and increases ET-1 plasma concen trations in conscious vats in a dose-dependent fashion. in spontaneously hy pertensive 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 myoglobinu ric 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 conclu sion, tezosentan, a potent mixed ET receptor antagonist with a short half-l ife, may offer a novel medical approach for the i.v. treatment of acute pat hological conditions.