title: Design, synthesis, and structure-activity relationships of aminopyridine N-oxides, a novel scaffold for the potent and selective inhibition of p38 mitogen activated protein kinase.
abstract: A novel series of aminopyridine N-oxides were designed, synthesized, and tested for their ability to inhibit p38alpha MAP kinase. Some of these compounds showed a significant reduction in the LPS-induced TNFalpha 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 a marked selectivity against other related kinases. Compound 45 was identified as a potent and selective p38alpha inhibitor with an appropriate balance between potency and pharmacokinetics. In vivo efficacy of 45 was demonstrated in reducing TNFalpha levels in an acute murine model of inflammation (ED(50) = 1 mg/kg in LPS-induced TNFalpha production when dosed orally 1.5 h prior to LPS administration). The oral efficacy of 45 was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally (ED(50) = 4.5 mg/kg).
authors.affiliation: Department of Medicinal Chemistry, Almirall Research Center, Almirall SA, Barcelona, Spain. wenceslao.lumeras@almirall.com
authors.forename: Wenceslao
authors.initials: W
authors.lastname: Lumeras
authors.forename: Francisco
authors.initials: F
authors.lastname: Caturla
authors.forename: Laura
authors.initials: L
authors.lastname: Vidal
authors.forename: Cristina
authors.initials: C
authors.lastname: Esteve
authors.forename: Cristina
authors.initials: C
authors.lastname: Balagué
authors.forename: Adelina
authors.initials: A
authors.lastname: Orellana
authors.forename: María
authors.initials: M
authors.lastname: Domínguez
authors.forename: Ramón
authors.initials: R
authors.lastname: Roca
authors.forename: Josep M
authors.initials: JM
authors.lastname: Huerta
authors.forename: Núria
authors.initials: N
authors.lastname: Godessart
authors.forename: Bernat
authors.initials: B
authors.lastname: Vidal
mesh_terms: D000631:Aminopyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001169:Arthritis, Experimental / Q000097:blood / Q000188:drug therapy; D020134:Catalytic Domain; D002460:Cell Line; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008958:Models, Molecular; D010087:Oxides / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000097:blood; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D000631:Aminopyridines; D010087:Oxides; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases