title: Nonpeptide endothelin receptor antagonists. VI: Pharmacological characterization of SB 217242, a potent and highly bioavailable endothelin receptor antagonist.
abstract: This study describes the pharmacological characterization of SB 217242, a highly potent orally bioavailable nonpeptide antagonist of both endothelin type A (ETA) and endothelin type B (ETB) receptors. In human cloned ETA and ETB receptors, SB 217242 produced concentration-dependent displacement of [125]I-endothelin-1 (ET-1) in both receptor subtypes with Ki values of 1.1 and 111 nM, respectively. SB 217242 produced concentration-dependent, parallel rightward shifts in the ET-1 concentration-response curves in rat isolated aorta and human isolated pulmonary artery (ETA receptor-mediated vascular contraction) with Kb values of 4.4 and 5.0 nM, respectively. SB 217242 was 4-, 62- and 125-fold more potent as an ETA receptor antagonist than the previously reported compounds BQ-123, PD 142893 and Ro 46-2005, respectively. SB 217242 (10 microM) did not produce significant effects against contraction produced by other vasoactive agents. SB 217242 produced concentration-dependent antagonism of responses produced by ETB receptor activation as demonstrated by antagonism of sarafotoxin S6c-mediated contraction in the rabbit isolated pulmonary artery with a Kb value of 352 nM. In vitro cell monolayers of Caco-2 cells had high permeability to SB 217242. In vivo pharmacokinetics in the rat confirmed that SB 217242 was rapidly absorbed from the gastrointestinal tract with a bioavailability of 66%. The SB 217242 plasma half-life in rats after intraduodenal administration was 3.3 hr, with a systemic clearance of 27.3 ml/min/kg. Orally administered SB 217242 (0.3-30 mg/kg) produced dose-dependent inhibition of the pressor response to exogenous ET-1 in conscious rats; with a dose of 30 mg/kg p.o., inhibition was observed for at least 5.5 hr. The present study demonstrates that SB 217242 is a highly potent antagonist of both ETA and ETB receptors. In addition, SB 217242 has high in vitro permeability and high oral bioavailability. SB 217242 represents a new orally active pharmacological tool that should assist in the elucidation of the chronic role of endothelin in pathophysiology.
authors.affiliation: Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, USA.
authors.forename: E H
authors.initials: EH
authors.lastname: Ohlstein
authors.forename: P
authors.initials: P
authors.lastname: Nambi
authors.forename: A
authors.initials: A
authors.lastname: Lago
authors.forename: D W
authors.initials: DW
authors.lastname: Hay
authors.forename: G
authors.initials: G
authors.lastname: Beck
authors.forename: K L
authors.initials: KL
authors.lastname: Fong
authors.forename: E P
authors.initials: EP
authors.lastname: Eddy
authors.forename: P
authors.initials: P
authors.lastname: Smith
authors.forename: H
authors.initials: H
authors.lastname: Ellens
authors.forename: J D
authors.initials: JD
authors.lastname: Elliott
mesh_terms: D000818:Animals; D001682:Biological Availability; D016466:CHO Cells; D018938:Caco-2 Cells; D002264:Carboxylic Acids / Q000493:pharmacokinetics / Q000494:pharmacology*; D006224:Cricetinae; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007189:Indans / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D010539:Permeability; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D002264:Carboxylic Acids; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D007189:Indans; C098288:enrasentan