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Titolo:
)OCTYL]OXY]-2-PYRIDINYL]METHYL]THIO]METHYL]BENZOIC ACID AND RELATED-COMPOUNDS - HIGH-AFFINITY LEUKOTRIENE B-4 RECEPTOR ANTAGONISTS
Autore:
DAINES RA; CHAMBERS PA; EGGLESTON DS; FOLEY JJ; GRISWOLD DE; HALTIWANGER RC; JAKAS DR; KINGSBURY WD; MARTIN LD; PENDRAK I; SCHMIDT DB; TZIMAS MN; SARAU HM;
Indirizzi:
SMITHKLINE BEECHAM PHARMACEUT,DEPT MED CHEM,POB 1539 KING OF PRUSSIA PA 19406 SMITHKLINE BEECHAM PHARMACEUT,DEPT PHARMACOL KING OF PRUSSIA PA 19406 SMITHKLINE BEECHAM PHARMACEUT,DEPT PHYS & STRUCT CHEM KING OF PRUSSIAPA 19406
Titolo Testata:
Journal of medicinal chemistry
fascicolo: 20, volume: 37, anno: 1994,
pagine: 3327 - 3336
SICI:
0022-2623(1994)37:20<3327:)AAR>2.0.ZU;2-7
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN POLYMORPHONUCLEAR LEUKOCYTES; NEUTROPHIL FUNCTIONS; ARACHIDONIC-ACID; INFLAMMATION; INHIBITOR; BINDING; METABOLISM; CALCIUM; CELLS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
40
Recensione:
Indirizzi per estratti:
Citazione:
R.A. Daines et al., ")OCTYL]OXY]-2-PYRIDINYL]METHYL]THIO]METHYL]BENZOIC ACID AND RELATED-COMPOUNDS - HIGH-AFFINITY LEUKOTRIENE B-4 RECEPTOR ANTAGONISTS", Journal of medicinal chemistry, 37(20), 1994, pp. 3327-3336

Abstract

)octyl]oxy]-2-pyridinyl]methyl]thio]methyl]benzoic acid (11, SB 201993) is a novel, potent LTB(4) receptor antagonist. Compound 11 arose from a structure-activity study of a series of trisubstituted pyridines that demonstrated LTB(4) receptor antagonist activity. The placement of an additional methylene unit in the sulfur containing chain linking the pyridine and benzoic acid moieties of lead compound 8(K-i=80 nM) resulted in a greater than 10-fold increase in receptor affinity. Additionally, in this new series of compounds, the oxidation state of the sulfur was found to be critical to the activity, i.e., the sulfoxide and sulfone showed substantially lower affinity for the LTB(4) receptor. Compound 11 competitively inhibits the binding of [H-3]LTB(4) to LTB(4) receptors on human polymorphonuclear leukocutes with a K-i of 7.1 nM and blocks both the LTB(4)-induced calcium mobilization and the LTB(4)-induced degranulation responses in these cells with IC50 values of 131 and 271 nM, respectively. Compound 11 demonstrated oral LTB(4) antagonist activity as well as topical antiinflammatory activity in the mouse.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 26/09/20 alle ore 07:47:10