TY - JOUR T1 - PF-03715455: An inhaled p38 inhibitor for the treatment of chronic obstructive pulmonary disease JF - European Respiratory Journal JO - Eur Respir J VL - 42 IS - Suppl 57 SP - 1764 AU - Iain Kilty AU - Nick Clarke AU - David Fairmain AU - David Lamb AU - John Mathias AU - David Millan AU - Karen Wright AU - Christelle Perros-Huguet AU - Mike Yeadon Y1 - 2013/09/01 UR - http://erj.ersjournals.com/content/42/Suppl_57/1764.abstract N2 - Rationale & Methods: There is an acute need for novel anti-inflammatory therapies for the treatment of COPD. A series of potent slow offset rapidly metabolised crystalline p38 inhibitors were identified and optimised for inhaled delivery. These compounds were screened in LPS / IL-1 induced primary monocyte and lung epithelial cells measuring a range of cytokines including TNFα, MIP1β, IL-6, IL-8. In addition, efficacy of IL-1 induced IL-8 inhibition in peripheral blood monocytes (PBMC) was compared to corticosteroids +/- co-incubation with cigarette smoke condensate (CSC). Topical in vivo activity was assessed in the dog segmental LPS challenge model.Results:The maximal efficacy of PF-03715455 in reducing IL-1 mediated IL-8 production in human PBMC was modestly decreased by oxidative stress in the form of CSC (from 92% to 81%, respectively), while the potency of PF-03715455 was decreased 1.9-fold. However, the maximal efficacy of fluticasone propionate was dramatically decreased in the presence of CSC (from 73% to 39%, respectively), with a concomitant 3.1-fold decrease in relative potency. 1mg inhaled dry powder PF-03715455 resulted in a 48% inhibition of segmental LPS induced neutrophilia in dog.Conclusion: PF-03715455 has broad anti-inflammatory effects in human lung cell systems and animal model systems and maintains activity under conditions of oxidative stress where corticosteroid efficacy is diminished. ER -