SD0006: a potent, selective and orally available inhibitor of p38 kinase.
SD0006 is a diarylpyrazole that was prepared as an inhibitor of p38 kinase-alpha (p38alpha). In vitro, SD0006 was selective for p38alpha kinase over 50 other kinases screened (including p38gamma and p38delta with modest selectivity over p38beta). Crystal structures with p38alpha show binding at the ATP site with additional residue interactions outside the ATP pocket unique to p38alpha that can confer advantages over other ATP competitive inhibitors. Direct correlation between inhibition of p38alpha activity and that of lipopolysaccharide-stimulated TNFalpha release was established in cellular models and in vivo, including a phase 1 clinical trial. Potency (IC(50)) for inhibiting tumor necrosis factor-alpha (TNFalpha) release, in vitro and in vivo, was <200 nmol/l. In vivo, SD0006 was effective in the rat streptococcal-cell-wall-induced arthritis model, with dramatic protective effects on paw joint integrity and bone density as shown by radiographic analysis. In the murine collagen-induced arthritis model, equivalence was demonstrated to anti-TNFalpha treatment. SD0006 also demonstrated good oral anti-inflammatory efficacy with excellent cross-species correlation between the rat, cynomolgus monkey, and human. SD0006 suppressed expression of multiple proinflammatory proteins at both the transcriptional and translational levels. These properties suggest SD0006 could provide broader therapeutic efficacy than cytokine-targeted monotherapeutics.
Burnette
Barry L
BL
Pfizer Global Research and Development, Pfizer, Chesterfield, Mo. 63017, USA. barry.l.burnette@pfizer.com
Selness
Shaun
S
Devraj
Raj
R
Jungbluth
Gail
G
Kurumbail
Ravi
R
Stillwell
Loreen
L
Anderson
Gary
G
Mnich
Stephen
S
Hirsch
Jeffrey
J
Compton
Robert
R
De Ciechi
Pamela
P
Hope
Heidi
H
Hepperle
Michael
M
Keith
Robert H
RH
Naing
Win
W
Shieh
Huey
H
Portanova
Joseph
J
Zhang
Yan
Y
Zhang
Jian
J
Leimgruber
Richard M
RM
Monahan
Joseph
J
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy*; D015519:Bone Density / Q000187:drug effects; D002460:Cell Line; D019446:Endotoxemia / Q000188:drug therapy / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008958:Models, Molecular; D010146:Pain / Q000188:drug therapy; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use*; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D011720:Pyrazoles; D011743:Pyrimidines; C545840:SD 0006; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases