title: p38 MAP kinase inhibitors. Part 5: discovery of an orally bio-available and highly efficacious compound based on the 7-amino-naphthyridone scaffold.
abstract: A new sub-class of p38 inhibitors represented by 7-amino-naphthyridone have been discovered. Benchmark compound 16 potently inhibited p38 in vitro, was functionally active, and displayed excellent pharmacokinetic profiles in two animal species. Compound 16 reduced inflammation in animal disease models at EC(50) doses as low as 0.2mpk.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. ravi_natarajan@merck.com
authors.forename: Swaminathan R
authors.initials: SR
authors.lastname: Natarajan
authors.forename: Luping
authors.initials: L
authors.lastname: Liu
authors.forename: Mark
authors.initials: M
authors.lastname: Levorse
authors.forename: James E
authors.initials: JE
authors.lastname: Thompson
authors.forename: Edward A
authors.initials: EA
authors.lastname: O'Neill
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: O'Keefe
authors.forename: Kalpit A
authors.initials: KA
authors.lastname: Vora
authors.forename: Raymond
authors.initials: R
authors.lastname: Cvetovich
authors.forename: John Y
authors.initials: JY
authors.lastname: Chung
authors.forename: Ester
authors.initials: E
authors.lastname: Carballo-Jane
authors.forename: Denise M
authors.initials: DM
authors.lastname: Visco
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D001682:Biological Availability; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000187:drug effects; D015394:Molecular Structure; D009000:Monocytes / Q000187:drug effects; D009287:Naphthyridines / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: C515127:7-amino-5-(2,4-difluorophenyl)-1-(2,6-difluorophenyl)-1,6-naphthyridin-1H-2-one; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D009287:Naphthyridines; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases