Pharmacology of endothelin receptor antagonists ABT-627, ABT-546, A-182086 and A-192621: ex vivo and in vivo studies.
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.
Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL 60064, U.S.A.
Jerry L
JL
Wessale
Andrew L
AL
Adler
Eugene I
EI
Novosad
Samuel V
SV
Calzadilla
Brian D
BD
Dayton
Kennan C
KC
Marsh
Martin
M
Winn
Hwan-Soo
HS
Jae
Thomas W
TW
von Geldern
Terry J
TJ
Opgenorth
J Ruth
JR
Wu-Wong
D000704:Analysis of Variance; D000818:Animals; D001011:Aorta; D000077868:Atrasentan; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008252:Macaca fascicularis; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D011759:Pyrrolidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D014757:Viper Venoms / Q000494:pharmacology
C467893:A 182086; C120508:A 192621; C467892:ABT 546; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013449:Sulfonamides; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; D000077868:Atrasentan