p38 Inhibitors: piperidine- and 4-aminopiperidine-substituted naphthyridinones, quinolinones, and dihydroquinazolinones.
We have synthesized a series of C7-piperidine- and 4-aminopiperidine-substituted naphthyridinones, quinolinones, and dihydroquinazolinones that are highly potent inhibitors of both p38MAP kinase activity and TNF-alpha release. The 4-aminopentamethylpiperidine naphthyridinone 5, which was designed to block metabolism at major 'hot spots', combined excellent inhibitory potency with good oral bioavailability in the rat.
Hunt
Julianne A
JA
Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA. julianne_hunt@merck.com
Kallashi
Florida
F
Ruzek
Rowena D
RD
Sinclair
Peter J
PJ
Ita
Ida
I
McCormick
Sherrie X
SX
Pivnichny
James V
JV
Hop
Cornelis E C A
CE
Kumar
Sanjeev
S
Wang
Zhen
Z
O'Keefe
Stephen J
SJ
O'Neill
Edward A
EA
Porter
Gene
G
Thompson
James E
JE
Woods
Andrea
A
Zaller
Dennis M
DM
Doherty
James B
JB
D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D019540:Area Under Curve; D001682:Biological Availability; D004285:Dogs; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006207:Half-Life; D008253:Macaca mulatta; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D015363:Quinolones / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D000890:Anti-Infective Agents; D004791:Enzyme Inhibitors; D009287:Naphthyridines; D010880:Piperidines; D011799:Quinazolines; D015363:Quinolones; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases