SB 209670, a rationally designed potent nonpeptide endothelin receptor antagonist

  • Proc Natl Acad Sci U S A. 1994 Aug 16;91(17):8052-6. doi: 10.1073/pnas.91.17.8052.
E H Ohlstein  1 ,  P Nambi ,  S A Douglas ,  R M Edwards ,  M Gellai ,  A Lago ,  J D Leber ,  R D Cousins ,  A Gao ,  J S Frazee
Affiliations
  • 1. Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939.
PMID: 8058755 DOI: 10.1073/pnas.91.17.8052
Abstract

An extremely potent and highly specific non-peptide, 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 ETA and ETB (Ki = 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.

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