Abstract
Endothelins (ETs), 21-amino-acid peptides involved in the pathogenesis of various diseases, bind to ET(A) and ET(B) receptors to initiate their effects. Based on the same core structure, we have developed four small-molecule ET receptor antagonists, ABT-627 (atrasentan), ABT-546, A-182086 and A-192621, which exhibit differences in selectivity for ET(A) and ET(B) receptors. In this report, we compare the efficacy, potency and pharmacokinetic properties of these four antagonists, including potency in inhibiting ET-1- or Sarafotoxin 6c-induced vessel constriction in isolated arteries and efficacy in antagonizing ET-1-, big ET-1- or Sarafotoxin 6c-induced pressor responses in rats.
MeSH terms
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Analysis of Variance
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Animals
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Aorta
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Atrasentan
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Dogs
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Dose-Response Relationship, Drug
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Endothelin Receptor Antagonists*
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Endothelin-1 / pharmacology
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Endothelium, Vascular / drug effects*
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Female
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Humans
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In Vitro Techniques
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Macaca fascicularis
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Male
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Muscle, Smooth, Vascular / drug effects*
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Pyrrolidines / pharmacokinetics
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Pyrrolidines / pharmacology*
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Rabbits
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Rats
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Rats, Sprague-Dawley
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Receptor, Endothelin A
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Receptor, Endothelin B
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Sulfonamides / pharmacokinetics
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Sulfonamides / pharmacology
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Vasoconstrictor Agents / pharmacology
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Vasodilator Agents / pharmacokinetics
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Vasodilator Agents / pharmacology*
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Viper Venoms / pharmacology
Substances
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A 182086
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A 192621
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ABT 546
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Endothelin Receptor Antagonists
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Endothelin-1
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Pyrrolidines
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Receptor, Endothelin A
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Receptor, Endothelin B
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Sulfonamides
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Vasoconstrictor Agents
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Vasodilator Agents
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Viper Venoms
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sarafotoxins s6
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Atrasentan