p38 MAP kinase inhibitors: metabolically stabilized piperidine-substituted quinolinones and naphthyridinones.
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.
Bao
Jianming
J
Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA. bao_jianming@merck.com
Hunt
Julianne A
JA
Miao
Shouwu
S
Rupprecht
Kathleen M
KM
Stelmach
John E
JE
Liu
Luping
L
Ruzek
Rowena D
RD
Sinclair
Peter J
PJ
Pivnichny
James V
JV
Hop
Cornelis E C A
CE
Kumar
Sanjeev
S
Zaller
Dennis M
DM
Shoop
Wesley L
WL
O'neill
Edward A
EA
O'keefe
Stephen J
SJ
Thompson
Chris M
CM
Cubbon
Rose M
RM
Wang
Ruixiu
R
Zhang
Wen Xiao
WX
Thompson
James E
JE
Doherty
James B
JB
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
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