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 (p38 alpha). In vitro, SD0006 was selective for p38 alpha kinase over 50 other kinases screened (including p38 gamma and p38 delta with modest selectivity over p38 beta). Crystal structures with p38 alpha show binding at the ATP site with additional residue interactions outside the ATP pocket unique to p38 alpha that can confer advantages over other ATP competitive inhibitors. Direct correlation between inhibition of p38 alpha activity and that of lipopolysaccharide-stimulated TNF alpha release was established in cellular models and in vivo, including a phase 1 clinical trial. Potency (IC50) for inhibiting tumor necrosis factor-alpha (TNF alpha) 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-TNF alpha 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. Copyright (C) 2009 S. Karger AG, Basel