Nonpeptide endothelin receptor antagonists. VI: Pharmacological characterization of SB 217242, a potent and highly bioavailable endothelin receptor antagonist.
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.
Ohlstein
E H
EH
Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, USA.
Nambi
P
P
Lago
A
A
Hay
D W
DW
Beck
G
G
Fong
K L
KL
Eddy
E P
EP
Smith
P
P
Ellens
H
H
Elliott
J D
JD
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
D002264:Carboxylic Acids; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D007189:Indans; C098288:enrasentan