SB-209670, A RATIONALLY DESIGNED POTENT NONPEPTIDE ENDOTHELIN RECEPTOR ANTAGONIST

An extremely potent and highly specific nonpeptide, subnanomolar endothelin (ET) receptor antagonist, SB 209670, has been synthesized and characterized. SB 209670, which was rationally designed using conformational models of ET-1, selectively inhibits binding of I-125-labeled ET-1 to cloned human ET receptor subtypes ET(A) and ET(B) (K-i = 0.2 and 18 nM, respectively). SB 209670 produces concentration-dependent inhibition of ET-1-mediated vasoconstriction in isolated vascular tissues and in vivo following either intravenous or intraduodenal administration. SB 209670 produces a dose-dependent reduction in blood pressure in hypertensive rats, protects from ischemia-induced neuronal degeneration in a gerbil stroke model, and attenuates neointima formation following rat carotid artery balloon angioplasty. SB 209670 will be useful in characterizing and classifying the physiological and pathophysiological effects of ET.