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Titolo:
In vitro and in vivo pharmacological characterization of SB 201993, an eicosanoid-like LTB4 receptor antagonist with anti-inflammatory activity
Autore:
Sarau, HM; Foley, JJ; Schmidt, DB; Martin, LD; Webb, EF; Tzimas, MN; Breton, JJ; Chabot-Fletcher, M; Underwood, DC; Hay, DWP; Kingsbury, WD; Chambers, PA; Pendrak, I; Jakas, DR; Sathe, GM; Van Horn, S; Daines, RA; Griswold, DE;
Indirizzi:
SmithKline Beecham Pharmaceut, Dept Pulm Pharmacol, King Of Prussia, PA 19406 USA SmithKline Beecham Pharmaceut King Of Prussia PA USA 19406 , PA 19406 USA SmithKline Beecham Pharmaceut, Dept Immunol, King Of Prussia, PA 19406 USASmithKline Beecham Pharmaceut King Of Prussia PA USA 19406 , PA 19406 USA SmithKline Beecham Pharmaceut, Dept Med Chem, King Of Prussia, PA 19406 USA SmithKline Beecham Pharmaceut King Of Prussia PA USA 19406 , PA 19406 USA SmithKline Beecham Pharmaceut, Dept Genet Technol, King Of Prussia, PA 19406 USA SmithKline Beecham Pharmaceut King Of Prussia PA USA 19406 , PA 19406 USA
Titolo Testata:
PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS
fascicolo: 1, volume: 61, anno: 1999,
pagine: 55 - 64
SICI:
0952-3278(199907)61:1<55:IVAIVP>2.0.ZU;2-#
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN POLYMORPHONUCLEAR LEUKOCYTES; LEUKOTRIENE B-4; ANTIINFLAMMATORY ACTIVITY; STRUCTURAL ANALOGS; BINDING ACTIVITY; HUMAN SKIN; CELL-LINE; ACTIVATION; ACID; GENERATION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
47
Recensione:
Indirizzi per estratti:
Indirizzo: Sarau, HM SmithKline Beecham Pharmaceut, Dept Pulm Pharmacol, 709 Swedeland Rd,POB 1539, King Of Prussia, PA 19406 USA SmithKline Beecham Pharmaceut 709 Swedeland Rd,POB 1539 King Of Prussia PA USA 19406
Citazione:
H.M. Sarau et al., "In vitro and in vivo pharmacological characterization of SB 201993, an eicosanoid-like LTB4 receptor antagonist with anti-inflammatory activity", PROS LEUK E, 61(1), 1999, pp. 55-64

Abstract

Leukotriene B-4 (LTB4) and 12-(R)-hydroxy-5,8,10,14-eicosatetraenoic acid (12-[R]-HETE) have been postulated to contribute to the pathophysiology of inflammatory diseases. SE 201993, (E)-3-[[[[6-(2-carboxyethenyl)-5-[[8-(4-methoxyphenyl)octyl] oxy]-2-pyridinyl] methyl] thio] methyl] benzoic acid, identified from a chemical series designed as ring-fused analogs of LTB4, was evaluated as an antagonist of LTB4- and 12-(R)-HETE-induced responses in vitro and for anti-inflammatory activity in vivo. SE 201993 competitively antagonized [(3)-H]-LTB4 binding to intact human neutrophils (K-i = 7.6 nM) and to membranes of RBL 2H3 cells expressing the LTB4 receptor (RBL 2H3-LTB4R; IC50 = 154 nM). This compound demonstrated competitive antagonism of LTB4- and 12-(R)-HETE-induced Ca2+ mobilization responses in human neutrophils (IC(50)s of 131 nM and 105 nM, respectively) and inhibited LTB4-induced Ca2+ mobilization in human cultured keratinocytes (IC50 = 61 nM), RBL 2H3-LTB4R cells (IC50 = 255 nM) and mouse neutrophils (IC50 = 410 nM). SE 201993 showed weak LTD4-receptor binding affinity (K-i = 1.9 mu M) and inhibited 5-lipoxygenase (IC50 of 3.6 mu M), both in vitro and ex vivo. In vivo, SE 201993 inhibited LTB4-induced neutrophil infiltration in mouse skin and produced dose-related, long lasting topical anti-inflammatory activity against the fluid and cellular phases of arachidonic acid-induced mouse ear inflammation (ED50 of 580 mu g/ear and 390 mu g/ear, respectively). Similarly, anti-inflammatory activity was also observed in the murine phorbol ester-induced cutaneous inflammation model (ED50 of 770 and 730 mu g/ear, respectively,against the fluid and cellular phases). These results indicate that SE 201993 blocks the actions of LTB4 and 12-(R)-HETE and inhibits a variety of inflammatory responses; and thus may be a useful compound to evaluate the role of these mediators in disease models.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 26/09/20 alle ore 07:02:12