Nonpeptide Endothelin Receptor Antagonists. Xi. Pharmacological Characterization Of Sb 234551, A High-Affinity And Selective Nonpeptide Eta Receptor Antagonist

The present study describes the pharmacological profile of ((E)-alpha-[[1-butyl-5-[2-[(2-carboxyphenyl)methoxy]-4-methoxy-phenyl]-1 H-pyrazol-4-yl]methlene]-6-methoxy-1,3-benzodioxole-5-propanoic acid) (SB 234551), a high-affinity, nonpeptide endothelin type A (ETA)-selective receptor antagonist. In human cloned ETA and endothelin type B (ETB) receptors, SE 234551 produced a concentration-dependent displacement of [I-125]-endothelin-1 with K-l values of 0.13 and 500 nM, respectively. SE 234551 elicited concentration-dependent, rightward competitive shifts in the endothelin-l concentration-response curves in isolated rat aorta and isolated human pulmonary artery (ETA receptor-mediated vascular contraction) with K-l values of 1.9 and 1.0 nM, respectively. SE 234551 antagonized ET, receptor-mediated vasoconstriction in the isolated rabbit pulmonary artery, as demonstrated by concentration-dependent, rightward shifts in the sarafotoxin S6c concentration-response curves (K-b = 555 nM). SE 234551 produced weak functional inhibition of sarafotoxin S6c-mediated endothelium-dependent relaxation (IC50 = 7 mu M). SE 234551 (10 mu M) had no significant effect against contraction produced by several other vasoactive agents and did not significantly influence radioligand binding to a number of diverse receptors. SE 234551 (0.1-1.0 mg/kg i.v.) dose-dependently inhibited the presser response to exogenous endothelin-l in conscious rats. In vivo pharmacokinetic analysis in the rat demonstrated that SE 234551 was rapidly absorbed from the GI tract with a bioavailability of 30%. SE 234551 had a plasma half-life of 125 min and a systemic clearance of 25.0 ml/min/kg. The present study demonstrates that SE 234551 is an antagonist with high affinity for the ET, receptor, while sparing the ET, receptor. SE 234551 is a new pharmacological tool that should assist in the elucidation of the role of endothelin in pathophysiology.