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-bromopyrimidin-4-yl)-4-(2-hydroxy-1, 1-dimethylethyl)benzensulfonamide sodium salt sesquihydrate (T-0201), a new nonpeptide endothelin (ET) receptor antagonist, in vitro and in vivo. In binding studies, T-0201 competitively antagonized the specific binding of [125I]-ET-1 to human cloned ETA receptors (the Ki value was 0.015 +/- 0.004 nM). T-0201 weakly inhibited [125I]-ET-1-binding to human cloned ETB receptors; the Ki value was 41 +/- 21 nM. T-0201 shifted the concentration-response curve of ET-1-induced contraction of the isolated rat aorta (ETA receptors) to the right (pA2 = 9.0 +/- 0.2). In the isolated rat trachea, a selective ETB agonist sarafotoxin S6c-induced contraction was inhibited by T-0201 (pA2 = 6.8 +/- 0.3). T-0201 also caused the inhibition of ET-1-induced contraction of the isolated rabbit pulmonary artery (pA2 = 5.7 +/- 0.3). In anesthetized rats, T-0201 (0.01-1 mg/kg) inhibited the pressor 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 significant inhibitory effect of orally administered T-0201 on big ET-1-induced pressor 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 potent, long-lasting, orally active and selective ETA receptor antagonist.
Hoshino
T
T
Lead Optimization Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama, Japan.
Yamauchi
R
R
Kikkawa
K
K
Yabana
H
H
Murata
S
S
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003001:Cloning, Molecular; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D006801:Humans; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011189:Potassium Chloride / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology*
D065128:Endothelin Receptor Antagonists; D007457:Iodine Radioisotopes; D011743:Pyrimidines; D013449:Sulfonamides; C113972:T 0201; D011189:Potassium Chloride