title: Pharmacological characterization of A-127722: an orally active and highly potent ETA-selective receptor antagonist.
abstract: Endothelins (ET) are potent vasoactive peptides implicated in the pathogenesis of a number of vascular diseases. The effects of ET on mammalian organs and cells are initiated by binding to ETA or ETB receptors. In this report, we document the pharmacology of A-127722, a novel ETA-selective receptor antagonist. A-127722 inhibits [125I]ET-1 binding to cloned human ETA and ETB receptors competitively with Ki values of 69 pM and 139 nM, respectively. A-127722 exhibits a dose-dependent inhibition of ET-1-induced arachidonic acid release in human pericardium smooth muscle cells with a pA2 value of 10.5 and inhibits ET-1-induced vasoconstriction in isolated rat aorta with a pA2 value of 9.2. In vivo, A-127722 dose-dependently blocks the pressor response to ET-1 (0.3 nmol/kg i.v.) in conscious rats. Statistically significant (P < .05) antagonism is seen at doses greater than 0.1 mg/kg p.o. Maximal inhibition, at 10 mg/kg, remains constant for at least 8 hr after dosing. No effect is seen on the ETB-mediated transient vasodepressor effect of exogenous ET-1. In conclusion, A-127722 is ETA-selective, orally bioavailable and efficacious for inhibiting the effects of ET in the rat, and A-127722 is the most potent ET receptor antagonist yet reported.
authors.affiliation: Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: Opgenorth
authors.forename: A L
authors.initials: AL
authors.lastname: Adler
authors.forename: S V
authors.initials: SV
authors.lastname: Calzadilla
authors.forename: W J
authors.initials: WJ
authors.lastname: Chiou
authors.forename: B D
authors.initials: BD
authors.lastname: Dayton
authors.forename: D B
authors.initials: DB
authors.lastname: Dixon
authors.forename: L J
authors.initials: LJ
authors.lastname: Gehrke
authors.forename: L
authors.initials: L
authors.lastname: Hernandez
authors.forename: S R
authors.initials: SR
authors.lastname: Magnuson
authors.forename: K C
authors.initials: KC
authors.lastname: Marsh
authors.forename: E I
authors.initials: EI
authors.lastname: Novosad
authors.forename: T W
authors.initials: TW
authors.lastname: Von Geldern
authors.forename: J L
authors.initials: JL
authors.lastname: Wessale
authors.forename: M
authors.initials: M
authors.lastname: Winn
authors.forename: J R
authors.initials: JR
authors.lastname: Wu-Wong
mesh_terms: D000284:Administration, Oral; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D000077868:Atrasentan; D016466:CHO Cells; D006224:Cricetinae; D004285:Dogs; D065128:Endothelin Receptor Antagonists; D005260:Female; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D010716:Phosphatidylinositols / Q000378:metabolism; D011759:Pyrrolidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D013237:Stereoisomerism; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D065128:Endothelin Receptor Antagonists; D010716:Phosphatidylinositols; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D016718:Arachidonic Acid; D000077868:Atrasentan