SB 209670, a rationally designed potent nonpeptide endothelin receptor antagonist.
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.
Ohlstein
E H
EH
Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939.
Nambi
P
P
Douglas
S A
SA
Edwards
R M
RM
Gellai
M
M
Lago
A
A
Leber
J D
JD
Cousins
R D
RD
Gao
A
A
Frazee
J S
JS
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001667:Binding, Competitive; D001794:Blood Pressure / Q000187:drug effects; D016466:CHO Cells; D002339:Carotid Arteries / Q000502:physiology; D003001:Cloning, Molecular; D006224:Cricetinae; D015195:Drug Design; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D007189:Indans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008638:Mesenteric Arteries / Q000502:physiology; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013997:Time Factors; D014162:Transfection; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D007189:Indans; D011994:Recombinant Proteins; C087551:1H-Indene-2-carboxylic acid, 1-(1,3-benzodioxol-5-yl)-3-(2- (carboxymethoxy)-4-methoxyphenyl)-2,3-dihydro-5-propoxy-, (1S,2R,3S)-