Tezosentan

Tezosentan (RO 610612) is an endothelin (ET) receptor antagonist, with pA₂s of 9.5, 7.7 for ET_A and ET_B receptors, respectively. IC50 & Target:pA2: 9.5 (ET_A receptor), 7.7 (ET_B receptor)^[1]. In Vitro: Affinity of Tezosentan for the ET receptors is assessed in different cells and tissues. Tezosentan inhibits the specific ¹²⁵I-labeled ET-1 binding to ETA receptors with an inhibitory potency (K_i) of 0.3 nM on CHO cells and of 18 nM on membranes of baculovirus-infected insect cells. Similarly, Tezosentan inhibits the specific binding of ¹²⁵I-labeled ET-1, ET-3, or sarafotoxin S6c to ET_B receptors with an inhibitory affinity of 10 to 21 nM. Tezosentan up to a concentration of 1 μM did not exhibit any binding inhibitory activity in 27 radioligand binding assays different from ET binding. On H1 central, 5-hydroxytryptamine2A, and vasopressin V1 receptors, Tezosentan (1 μM) induces a weak inhibition of less than 20%^[1]. In Vivo: In pithed Wistar rats, Tezosentan dose-dependently inhibits the pressor effect of big ET-1 (P<0.001 at all doses). At the lowest dose tested of 1 mg/kg, Tezosentan inhibits the pressor effect of the various doses of big ET-1 by 50 to 80%. Tezosentan has no effect by itself on blood pressure in these pithed rats. Tezosentan is very effective in a rat model of acute renal failure. ET antagonists have been shown to prevent the vasoconstriction and the renal failure that follow acute renal ischemia in rats^[1].