SB 209670, a rationally designed potent nonpeptide endothelin receptor antagonist.

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.

• Authors: E H Ohlstein, P Nambi, S A Douglas, R M Edwards, M Gellai, A Lago, J D Leber, R D Cousins, A Gao, J S Frazee
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 91 Issue 17 Pg. 8052-6 (Aug 16 1994) ISSN: 0027-8424 [Print] United States
• PMID: 8058755 (Publication Type: Journal Article)

Chemical References

• Endothelin Receptor Antagonists
• Endothelins
• Indans
• Recombinant Proteins
• 1H-Indene-2-carboxylic acid, 1-(1,3-benzodioxol-5-yl)-3-(2- (carboxymethoxy)-4-methoxyphenyl)-2,3-dihydro-5-propoxy-, (1S,2R,3S)-

Topics

• Animals
• Aorta (drug effects, physiology)
• Binding, Competitive
• Blood Pressure (drug effects)
• CHO Cells
• Carotid Arteries (physiology)
• Cloning, Molecular
• Cricetinae
• Drug Design
• Endothelin Receptor Antagonists
• Endothelins (metabolism)
• Heart Rate (drug effects)
• Hemodynamics (drug effects)
• Humans
• In Vitro Techniques
• Indans (chemical synthesis, chemistry, pharmacology)
• Kinetics
• Male
• Mesenteric Arteries (physiology)
• Molecular Structure
• Muscle Contraction (drug effects, physiology)
• Muscle, Smooth, Vascular (drug effects, physiology)
• Pulmonary Artery (drug effects, physiology)
• Rabbits
• Radioligand Assay
• Rats
• Rats, Inbred SHR
• Rats, Sprague-Dawley
• Recombinant Proteins (antagonists & inhibitors)
• Time Factors
• Transfection
• Vascular Resistance (drug effects)
• Vasoconstriction (drug effects)