Discovery and evaluation of 7-alkyl-1,5-bis-aryl-pyrazolopyridinones as highly potent, selective, and orally efficacious inhibitors of p38alpha mitogen-activated protein kinase.
The p38alpha mitogen-activated protein (MAP) kinase is a central signaling molecule in many proinflammatory pathways, regulating the cellular response to a multitude of external stimuli including heat, ultraviolet radiation, osmotic shock, and a variety of cytokines especially interleukin-1beta and tumor necrosis factor alpha. Thus, inhibitors of this enzyme are postulated to have significant therapeutic potential for the treatment of rheumatoid arthritis, inflammatory bowel disease, and Crohn's disease, as well as other diseases where aberrant cytokine signaling is the driver of disease. In this communication, we describe a novel class of 7-alkyl-1,5-bis-aryl-pyrazolopyridinone-based p38alpha inhibitors. In particular, compound 3f is highly potent in the enzyme and cell-based assays, selective in an Ambit kinase screen, and efficacious (ED(50) < or = 0.01 mg/kg) in the rat collagen induced arthritis (CIA) model.
Pettus
Liping H
LH
Departments of Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. lpettus@amgen.com
Wurz
Ryan P
RP
Xu
Shimin
S
Herberich
Brad
B
Henkle
Bradley
B
Liu
Qiurong
Q
McBride
Helen J
HJ
Mu
Sharon
S
Plant
Matthew H
MH
Saris
Christiaan J M
CJ
Sherman
Lisa
L
Wong
Lu Min
LM
Chmait
Samer
S
Lee
Matthew R
MR
Mohr
Christopher
C
Hsieh
Faye
F
Tasker
Andrew S
AS
D000284:Administration, Oral; D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000188:drug therapy; D003094:Collagen / Q000494:pharmacology; D055808:Drug Discovery; D006801:Humans; D008297:Male; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D011728:Pyridones / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D047428:Protein Kinase Inhibitors; D011728:Pyridones; D003094:Collagen; D048308:Mitogen-Activated Protein Kinase 14