p38 MAP kinase inhibitors. Part 5: discovery of an orally bio-available and highly efficacious compound based on the 7-amino-naphthyridone scaffold.
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.
Natarajan
Swaminathan R
SR
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. ravi_natarajan@merck.com
Liu
Luping
L
Levorse
Mark
M
Thompson
James E
JE
O'Neill
Edward A
EA
O'Keefe
Stephen J
SJ
Vora
Kalpit A
KA
Cvetovich
Raymond
R
Chung
John Y
JY
Carballo-Jane
Ester
E
Visco
Denise M
DM
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*
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