title: 1,7-Naphthyridine 1-oxides as novel potent and selective inhibitors of p38 mitogen activated protein kinase.
abstract: The design, synthesis, and ability to inhibit p38α MAP kinase by a novel series of naphthyridine N-oxides will be described. Some of these compounds showed a significant reduction in the LPS-induced TNFα production in human whole blood. Structure-activity relationship studies revealed that N-oxide oxygen was essential for activity and was probably a determinant factor for its marked selectivity against other related kinases. After an extensive SAR exercise, several compounds from this series were identified as very potent p38α inhibitors. In vivo efficacy of some derivatives was demonstrated to reduce TNFα levels in an acute murine model of inflammation (ED(50) = 0.5 mg/kg in LPS-induced TNFα production when dosed orally 1.5 h prior to LPS administration). The oral efficacy was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally (ED(50) < 1 mg/kg).
authors: Department of Medicinal Chemistry, Almirall Research Center , Almirall S.A., Ctra. Laureà Miró 408, E-08980 Sant Feliu de Llobregat, Barcelona, Spain.
authors: Wenceslao
authors: W
authors: Lumeras
authors: Laura
authors: L
authors: Vidal
authors: Bernat
authors: B
authors: Vidal
authors: Cristina
authors: C
authors: Balagué
authors: Adelina
authors: A
authors: Orellana
authors: Mónica
authors: M
authors: Maldonado
authors: María
authors: M
authors: Domínguez
authors: Víctor
authors: V
authors: Segarra
authors: Francisco
authors: F
authors: Caturla
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy; D001665:Binding Sites; D002460:Cell Line; D018360:Crystallography, X-Ray; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000209:etiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D008070:Lipopolysaccharides; D009287:Naphthyridines; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases