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Titolo:
NONPEPTIDE ENDOTHELIN RECEPTOR ANTAGONISTS .6. PHARMACOLOGICAL CHARACTERIZATION OF SE-217242, A POTENT AND HIGHLY BIOAVAILABLE ENDOTHELIN RECEPTOR ANTAGONIST
Autore:
OHLSTEIN EH; NAMBI P; LAGO A; HAY DWP; BECK G; FONG KL; EDDY EP; SMITH P; ELLENS H; ELLIOTT JD;
Indirizzi:
SMITHKLINE BEECHAM PHARMACEUT,DEPT CARDIOVASC PHARMACOL,UW 2510,709 SWEDELAND RD KING OF PRUSSIA PA 19406 SMITHKLINE BEECHAM PHARMACEUT,DEPT CARDIOVASC KING OF PRUSSIA PA 19406 SMITHKLINE BEECHAM PHARMACEUT,DEPT RENAL KING OF PRUSSIA PA 19406 SMITHKLINE BEECHAM PHARMACEUT,DEPT PULM KING OF PRUSSIA PA 19406 SMITHKLINE BEECHAM PHARMACEUT,DEPT PHARMACOL KING OF PRUSSIA PA 19406 SMITHKLINE BEECHAM PHARMACEUT,DEPT DRUG DELIVERY KING OF PRUSSIA PA 19406 SMITHKLINE BEECHAM PHARMACEUT,DEPT DRUG METAB KING OF PRUSSIA PA 19406 SMITHKLINE BEECHAM PHARMACEUT,DEPT MED CHEM KING OF PRUSSIA PA 19406
Titolo Testata:
The Journal of pharmacology and experimental therapeutics
fascicolo: 2, volume: 276, anno: 1996,
pagine: 609 - 615
SICI:
0022-3565(1996)276:2<609:NERA.P>2.0.ZU;2-T
Fonte:
ISI
Lingua:
ENG
Soggetto:
CACO-2 CELL MONOLAYERS; TRANSPORT; LINE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
32
Recensione:
Indirizzi per estratti:
Citazione:
E.H. Ohlstein et al., "NONPEPTIDE ENDOTHELIN RECEPTOR ANTAGONISTS .6. PHARMACOLOGICAL CHARACTERIZATION OF SE-217242, A POTENT AND HIGHLY BIOAVAILABLE ENDOTHELIN RECEPTOR ANTAGONIST", The Journal of pharmacology and experimental therapeutics, 276(2), 1996, pp. 609-615

Abstract

This study describes the pharmacological characterization of SE 217242, a highly potent orally bioavailable nonpeptide antagonist of both endothelin type A (ET(A)) and endothelin type B (ET(B)) receptors. In human cloned ET(A) and ET(B) receptors, SE 217242 produced concentration-dependent displacement of [(125)]I-endothelin-1 (ET-1) in both receptor subtypes with K-i values of 1.1 and 111 nM, respectively. SE 217242 produced concentration-dependent, parallel rightward shifts in the ET-1 concentration-response curves in rat isolated aorta and human isolated pulmonary artery (ET(A) receptor-mediated vascular contraction) with K-b values of 4.4 and 5.0 nM, respectively. SB 217242 was 4-, 62- and 125-fold more potent as an ET(A) receptor antagonist than the previously reported compounds BQ-123, PD 142893 and Ro 46-2005, respectively. SB 217242 (10 mu M) did not produce significant effects against contraction produced by other vasoactive agents. SE 217242 produced concentration-dependent antagonism of responses produced by ET(B) receptoractivation as demonstrated by antagonism of sarafotoxin S6c-mediated contraction in the rabbit isolated pulmonary artery with a K-b value of 352 nM. In vitro cell monolayers of Caco-2 cells had high permeability to SE 217242. In vivo pharmacokinetics in the rat confirmed that SE217242 was rapidly absorbed from the gastrointestinal tract with a bioavailability of 66%. The SE 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 SE 217242 (0.3-30 mg/kg) produced dose-dependent inhibition of the presser 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 SE 217242 is a highly potent antagonist of both ET(A) and ET(B) receptors. In addition, SB 217242 has high in vitro permeability and high oral bioavailability. SE 217242 represents a new orally active pharmacological tool that should assist in the elucidation of the chronic role of endothelin in pathophysiology.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 04/04/20 alle ore 12:09:16