Abstract
The present study describes the pharmacological profile of ((E)-alpha-[[1-butyl-5-[2-[(2-carboxyphenyl)methoxy]-4-methoxy-phenyl]-1H-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, SB 234551 produced a concentration-dependent displacement of [125I]-endothelin-1 with Ki values of 0.13 and 500 nM, respectively. SB 234551 elicited concentration-dependent, rightward competitive shifts in the endothelin-1 concentration-response curves in isolated rat aorta and isolated human pulmonary artery (ETA receptor-mediated vascular contraction) with Kb values of 1.9 and 1.0 nM, respectively. SB 234551 antagonized ETBreceptor-mediated vasoconstriction in the isolated rabbit pulmonary artery, as demonstrated by concentration-dependent, rightward shifts in the sarafotoxin S6c concentration-response curves (Kb = 555 nM). SB 234551 produced weak functional inhibition of sarafotoxin S6c-mediated endothelium-dependent relaxation (IC50 = 7 μM). SB 234551 (10 μM) 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. SB 234551 (0.1–1.0 mg/kg i.v.) dose-dependently inhibited the pressor response to exogenous endothelin-1 in conscious rats. In vivo pharmacokinetic analysis in the rat demonstrated that SB 234551 was rapidly absorbed from the GI tract with a bioavailability of 30%. SB 234551 had a plasma half-life of 125 min and a systemic clearance of 25.0 ml/min/kg. The present study demonstrates that SB 234551 is an antagonist with high affinity for the ETA receptor, while sparing the ETB receptor. SB 234551 is a new pharmacological tool that should assist in the elucidation of the role of endothelin in pathophysiology.
Footnotes
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Send reprint requests to: Eliot H. Ohlstein, Ph.D., Department of Cardiovascular Pharmacology, UW 2511, SmithKline Beecham Pharmaceuticals, 709 Swedeland Road, King of Prussia, PA 19406.
- Abbreviations:
- ET-1
- endothelin-1
- ET-3
- endothelin-3
- S6c
- sarafotoxin S6c
- ETA receptor
- endothelin type A receptor
- ETB receptor
- endothelin type B receptor
- SB 234551
- ((E)-alpha-[[1-butyl-5-[2-[(2-carboxyphenyl)methoxy]-4-methoxy-phenyl]-1H-pyrazol-4-yl]methlene]-6-methoxy-1,3-benzodioxole-5-propanoic acid)
- Received August 1, 1997.
- Accepted April 29, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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