Discovery of pyridazinopyridinones as potent and selective p38 mitogen-activated protein kinase inhibitors.
The p38 mitogen-activated protein kinase (MAPK) plays an important role in the production of proinflammatory cytokines, making it an attractive target for the treatment of various inflammatory diseases. A series of pyridazinopyridinone compounds were designed as novel p38 kinase inhibitors. A structure-activity investigation identified several compounds possessing excellent potency in both enzyme and human whole blood assays. Among them, compound 31 exhibited good pharmacokinetic properties and showed excellent selectivity against other related kinases. In addition, 31 demonstrated efficacy in a collagen-induced arthritis disease model in rats.
Wu
Bin
B
Department of Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. binw@amgen.com
Wang
Hui-Ling
HL
Pettus
Liping
L
Wurz
Ryan P
RP
Doherty
Elizabeth M
EM
Henkle
Bradley
B
McBride
Helen J
HJ
Saris
Christiaan J M
CJ
Wong
Lu Min
LM
Plant
Matthew H
MH
Sherman
Lisa
L
Lee
Matthew R
MR
Hsieh
Faye
F
Tasker
Andrew S
AS
D051698:Activating Transcription Factor 2 / Q000378:metabolism; D000818:Animals; D018501:Antirheumatic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy; D001665:Binding Sites; D003094:Collagen; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008958:Models, Molecular; D010766:Phosphorylation; D011724:Pyridazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011728:Pyridones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D051698:Activating Transcription Factor 2; D018501:Antirheumatic Agents; D016209:Interleukin-8; D008070:Lipopolysaccharides; C552338:N-cyclopropyl-3-(8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido(3,2-d)pyridazin-3-yl)-4-methylbenzamide; D011724:Pyridazines; D011728:Pyridones; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen; D048051:p38 Mitogen-Activated Protein Kinases