title: p38 Inhibitors: piperidine- and 4-aminopiperidine-substituted naphthyridinones, quinolinones, and dihydroquinazolinones.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA. julianne_hunt@merck.com
authors.forename: Julianne A
authors.initials: JA
authors.lastname: Hunt
authors.forename: Florida
authors.initials: F
authors.lastname: Kallashi
authors.forename: Rowena D
authors.initials: RD
authors.lastname: Ruzek
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Sinclair
authors.forename: Ida
authors.initials: I
authors.lastname: Ita
authors.forename: Sherrie X
authors.initials: SX
authors.lastname: McCormick
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: Zhen
authors.initials: Z
authors.lastname: Wang
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: O'Keefe
authors.forename: Edward A
authors.initials: EA
authors.lastname: O'Neill
authors.forename: Gene
authors.initials: G
authors.lastname: Porter
authors.forename: James E
authors.initials: JE
authors.lastname: Thompson
authors.forename: Andrea
authors.initials: A
authors.lastname: Woods
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Zaller
authors.forename: James B
authors.initials: JB
authors.lastname: Doherty
mesh_terms: 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
chemical_list: 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