SB 209670, a rationally designed potent nonpeptide endothelin receptor antagonist

Eliot H. Ohlstein, Ponnal Nambi, Stephen A. Douglas, Richard M. Edwards, Miklos Gellai, Amparo Lago, Jack D. Leber, Russell D. Cousins, Aiming Gao, James S. Frazee, Catherine E. Peishoff, John W. Bean, Drake S. Eggleston, Nabil A. Elshourbagy, Chandrika Kumar, Jonathan A. Lee, Tian Li Yue, Calvert Louden, David P. Brooks, Joseph WeinstockGiora Feuerstein, George Poste, Robert R. Ruffolo, John G. Gleason, John D. Elliott

Research output: Contribution to journalArticle

176 Scopus citations

Abstract

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 125I-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.

Original languageEnglish (US)
Pages (from-to)8052-8056
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume91
Issue number17
DOIs
StatePublished - Aug 16 1994
Externally publishedYes

ASJC Scopus subject areas

  • General

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