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In vitro, SD0006 was selective for p38\u03b1 kinase over 50 other kinases screened (including p38\u03b3 and p38\u03b4 with modest selectivity over p38\u03b2). Crystal structures with p38\u03b1 show binding at the ATP site with additional residue interactions outside the ATP pocket unique to p38\u03b1 that can confer advantages over other ATP competitive inhibitors. Direct correlation between inhibition of p38\u03b1 activity and that of lipopolysaccharide-stimulated TNF\u03b1 release was established in cellular models and in vivo, including a phase 1 clinical trial. Potency (IC&lt;sub&gt;50&lt;\/sub&gt;) for inhibiting tumor necrosis factor-\u03b1 (TNF\u03b1) release, in vitro and in vivo, was &lt;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\u03b1 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.<\/jats:p>","DOI":"10.1159\/000227286","type":"journal-article","created":{"date-parts":[[2009,7,7]],"date-time":"2009-07-07T14:59:48Z","timestamp":1246978788000},"page":"42-60","source":"Crossref","is-referenced-by-count":30,"title":["SD0006: A Potent, Selective and Orally Available Inhibitor of p38 Kinase"],"prefix":"10.1159","volume":"84","author":[{"given":"Barry 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