title: p38 MAP kinase inhibitors: metabolically stabilized piperidine-substituted quinolinones and naphthyridinones.
abstract: Quinolinones and naphthyridinones with C7 N-t-butyl piperidine substituents were found to be potent p38 MAP kinase inhibitors. These compounds significantly suppress TNF-alpha release in both cellular and LPS-stimulated whole blood assays. They also displayed excellent PK profiles across three animal species. Quinolinone at 10 mpk showed comparable oral efficacy to that of dexamethasone at 1 mpk in a murine collagen-induced arthritis model.
authors.affiliation: Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA. bao_jianming@merck.com
authors.forename: Jianming
authors.initials: J
authors.lastname: Bao
authors.forename: Julianne A
authors.initials: JA
authors.lastname: Hunt
authors.forename: Shouwu
authors.initials: S
authors.lastname: Miao
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Rupprecht
authors.forename: John E
authors.initials: JE
authors.lastname: Stelmach
authors.forename: Luping
authors.initials: L
authors.lastname: Liu
authors.forename: Rowena D
authors.initials: RD
authors.lastname: Ruzek
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Sinclair
authors.forename: James V
authors.initials: JV
authors.lastname: Pivnichny
authors.forename: Cornelis E C A
authors.initials: CE
authors.lastname: Hop
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Kumar
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Zaller
authors.forename: Wesley L
authors.initials: WL
authors.lastname: Shoop
authors.forename: Edward A
authors.initials: EA
authors.lastname: O'neill
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: O'keefe
authors.forename: Chris M
authors.initials: CM
authors.lastname: Thompson
authors.forename: Rose M
authors.initials: RM
authors.lastname: Cubbon
authors.forename: Ruixiu
authors.initials: R
authors.lastname: Wang
authors.forename: Wen Xiao
authors.initials: WX
authors.lastname: Zhang
authors.forename: James E
authors.initials: JE
authors.lastname: Thompson
authors.forename: James B
authors.initials: JB
authors.lastname: Doherty
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental; D003094:Collagen / Q000737:chemistry; D003907:Dexamethasone / Q000737:chemistry; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000882:Haplorhini; D006801:Humans; D020128:Inhibitory Concentration 50; D008070:Lipopolysaccharides / Q000378:metabolism; D051379:Mice; D008956:Models, Chemical; D009287:Naphthyridines / Q000737:chemistry*; D010880:Piperidines / Q000737:chemistry*; D015363:Quinolones / Q000737:chemistry*; D051381:Rats; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000737:chemistry; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D009287:Naphthyridines; D010880:Piperidines; D015363:Quinolones; D014409:Tumor Necrosis Factor-alpha; C032727:piperidine; D003907:Dexamethasone; D003094:Collagen; D048051:p38 Mitogen-Activated Protein Kinases