1. Academic Validation
  2. SD0006: a potent, selective and orally available inhibitor of p38 kinase

SD0006: a potent, selective and orally available inhibitor of p38 kinase

  • Pharmacology. 2009;84(1):42-60. doi: 10.1159/000227286.
Barry L Burnette 1 Shaun Selness Raj Devraj Gail Jungbluth Ravi Kurumbail Loreen Stillwell Gary Anderson Stephen Mnich Jeffrey Hirsch Robert Compton Pamela De Ciechi Heidi Hope Michael Hepperle Robert H Keith Win Naing Huey Shieh Joseph Portanova Yan Zhang Jian Zhang Richard M Leimgruber Joseph Monahan
Affiliations

Affiliation

  • 1 Pfizer Global Research and Development, Pfizer, Chesterfield, Mo. 63017, USA. barry.l.burnette@pfizer.com
Abstract

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.

Figures
Products