Discovery of N-substituted pyridinones as potent and selective inhibitors of p38 kinase.
The identification and evolution of a series of potent and selective p38 inhibitors is described. p38 inhibitors based on a N-benzyl pyridinone high-throughput screening hit were prepared and their SAR explored. Their design was guided by ligand bound co-crystals of p38alpha. These efforts resulted in the identification of 12r and 19 as orally active inhibitors of p38 with significant efficacy in both acute and chronic models of inflammation.
Selness
Shaun R
SR
Department of Medicinal Chemistry, Pfizer Corporation, 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA. shaun.r.selness@pfizer.com
Devraj
Rajesh V
RV
Monahan
Joseph B
JB
Boehm
Terri L
TL
Walker
John K
JK
Devadas
Balekudru
B
Durley
Richard C
RC
Kurumbail
Ravi
R
Shieh
Huey
H
Xing
Li
L
Hepperle
Michael
M
Rucker
Paul V
PV
Jerome
Kevin D
KD
Benson
Alan G
AG
Marrufo
Laura D
LD
Madsen
Heather M
HM
Hitchcock
Jeff
J
Owen
Tom J
TJ
Christie
Lance
L
Promo
Michele A
MA
Hickory
Brian S
BS
Alvira
Edgardo
E
Naing
Win
W
Blevis-Bal
Radhika
R
D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases