DISCOVERY OF TBC11251, A POTENT, LONG-ACTING, ORALLY-ACTIVE ENDOTHELIN RECEPTOR-A SELECTIVE ANTAGONIST

Previously we reported the discovery of amidothiophenesulfonamides as endothelin receptor-A antagonists with high potency and selectivity. R eplacement of an amide group in this class of compounds with an acetyl group maintained the in vitro binding affinity and in vivo activity w hile providing a compound with oral bioavailability and longer duratio n of action. The optimal compound discovered during these studies, 15q (TBC11251), binds competitively to human ETA receptors with a K-i of 0.43 +/- 0.03 nM and an IC50 of 1.4 nM (IC50 for ETB = 9800 nM). This compound inhibits ET-1-induced stimulation of phosphoinositide turnove r with a K-i of 0.686 nM and a pA(2) of 8.0. The compound has a serum half-life in the rat and the dog of 6-7 h and 60-100% oral bioavailabi lity. This compound is one of the most selective ETA antagonists repor ted and therefore is suitable for additional pharmacological and clini cal investigation of the role of ETA receptors in diseases.