Anti-inflammatory properties of a novel N-phenyl pyridinone inhibitor of p38 mitogen-activated protein kinase: preclinical-to-clinical translation.
Signal transduction through the p38 mitogen-activated protein (MAP) kinase pathway is central to the transcriptional and translational control of cytokine and inflammatory mediator production. p38 MAP kinase inhibition hence constitutes a promising therapeutic strategy for treatment of chronic inflammatory diseases, based upon its potential to inhibit key pathways driving the inflammatory and destructive processes in these debilitating diseases. The present study describes the pharmacological properties of the N-phenyl pyridinone p38 MAP kinase inhibitor benzamide [3- [3-bromo-4-[(2,4-difluorophenyl)methoxy]-6-methyl-2- oxo-1(2H)-pyridinyl]-N,4-dimethyl-, (-)-(9CI); PH-797804]. PH-797804 is an ATP-competitive, readily reversible inhibitor of the alpha isoform of human p38 MAP kinase, exhibiting a K(i) = 5.8 nM. In human monocyte and synovial fibroblast cell systems, PH-797804 blocks inflammation-induced production of cytokines and proinflammatory mediators, such as prostaglandin E(2), at concentrations that parallel inhibition of cell-associated p38 MAP kinase. After oral dosing, PH-797804 effectively inhibits acute inflammatory responses induced by systemically administered endotoxin in both rat and cynomolgus monkeys. Furthermore, PH-797804 demonstrates robust anti-inflammatory activity in chronic disease models, significantly reducing both joint inflammation and associated bone loss in streptococcal cell wall-induced arthritis in rats and mouse collagen-induced arthritis. Finally, PH-797804 reduced tumor necrosis factor-alpha and interleukin-6 production in clinical studies after endotoxin administration in a dose-dependent manner, paralleling inhibition of the target enzyme. Low-nanomolar biochemical enzyme inhibition potency correlated with p38 MAP kinase inhibition in human cells and in vivo studies. In addition, a direct correspondence between p38 MAP kinase inhibition and anti-inflammatory activity was observed with PH-797804, thus providing confidence in dose projections for further human studies in chronic inflammatory disease.
Hope
Heidi R
HR
Discovery Biology, Inflammation Research, Pfizer Global Research and Development, Chesterfield, Missouri 63017, USA. heidi.r.hope@pfizer.com
Anderson
Gary D
GD
Burnette
Barry L
BL
Compton
Robert P
RP
Devraj
Rajesh V
RV
Hirsch
Jeffrey L
JL
Keith
Robert H
RH
Li
Xiong
X
Mbalaviele
Gabriel
G
Messing
Dean M
DM
Saabye
Matthew J
MJ
Schindler
John F
JF
Selness
Shaun R
SR
Stillwell
Loreen I
LI
Webb
Elizabeth G
EG
Zhang
Jian
J
Monahan
Joseph B
JB
D000293:Adolescent; D000328:Adult; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology; D001549:Benzamides / Q000097:blood / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D015519:Bone Density / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood; D015232:Dinoprostone / Q000096:biosynthesis; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D010010:Osteoclasts / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D011728:Pyridones; D011753:Pyrones / Q000097:blood / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D018746:Systemic Inflammatory Response Syndrome / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology; D055815:Young Adult; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001549:Benzamides; D016207:Cytokines; D008070:Lipopolysaccharides; C542398:PH 797804; D011728:Pyridones; D011753:Pyrones; D048051:p38 Mitogen-Activated Protein Kinases; D015232:Dinoprostone