PHARMACOLOGICAL PROFILE OF T-0201, A HIGHLY POTENT AND ORALLY-ACTIVE ENDOTHELIN RECEPTOR ANTAGONIST

The authors studied the pharmacological properties of N-(6-(2-(5-bromo pyrimidin-4-yl)-4-(2-hydroxy-1, 1-dimethylethyl)benzensulfonamide sodi um salt sesquihydrate (T-0201), a new nonpeptide endothelin (ET) recep tor antagonist, in vitro and in vivo. In binding studies, T-0201 compe titively antagonized the specific binding of [I-125]-ET-1 to human clo ned ET,receptors (the K-l value was 0.015 +/- 0.004 nM). T-0201 weakly inhibited [(125)]-ET-1-binding to human cloned ETB receptors; the K-l value was 41 +/- 21 nM. T-0201 shifted the concentration-response cur ve of ET-I-induced contraction of the isolated rat aorta (ET, receptor s) to the right (pA(2) = 9.0 +/- 0.2). In the isolated rat trachea, a selective ETB agonist sarafotoxin S6c-induced contraction was inhibite d by T-0201 (pA(2) = 6.8 +/- 0.3). T-0201 also caused the inhibition o f ET-I-induced contraction of the isolated rabbit pulmonary artery (pA (2) = 5.7 +/- 0.3). in anesthetized rats, T-0201 (0.01-1 mg/kgj inhibi ted the presser response to exogenous big ET-1 (1 nmol/kg i.v.), after both i.v. and p.o. administration, in a dose-dependent manner. The si gnificant inhibitory effect of orally administered T-0201 on big ET-1- induced presser response lasted for 4 hr at 0.1 mg/kg and for 8 hr at 1 mg/kg. Thus the present study demonstrates that T-0201 is a highly p otent, long-lasting, orally active and selective ETB receptor antagoni st.