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Oral phosphodiesterase (PDE) 4 inhibitors such as roflumilast have established the potential of PDE4 inhibition for the treatment of respiratory diseases. However, PDE4 inhibitor efficacy is limited by mechanism-related side effects such as emesis and nausea. Delivering the inhibitor by the inhaled route may improve therapeutic index, and herein we describe GSK256066 (6-({3[(dimethylamino) carbonyl]phenyl} sulfonyl)-8-methyl-4-{[3-methyloxy) phenyl]amino}-3quinolinecarboxamide), an exceptionally high affinity inhibitor of PDE4 designed for inhaled administration. GSK256066 is a slowand tight-binding inhibitor of PDE4B (apparent IC50 3.2 pM, steady state IC50 < 0.5pM), more potent than any previously documented compound, for example roflumilast (IC50 390 pM), tofimilast (IC50 1.6 nM) and cilomilast (IC50 74 nM). Consistent with this, GSK256066 inhibited TNFα production by lipopolysaccharide (LPS) stimulated human peripheral blood monocytes with 0.01nM IC50 (compared with IC50s of 5, 22 and 389nM for roflumilast, tofimilast and cilomilast) and by LPS-stimulated whole blood with 126 pM IC50. GSK256066 was highly selective for PDE4 (>380,000-fold vs PDEs 1, 2, 3, 5 and 6 and >2500-fold against PDE7), inhibited PDE4 isoforms A-D with equal affinity and had a high HARBS (High-Affinity Rolipram Binding Site) ratio (>17). When administered by the intratracheal route to rats, GSK256066 inhibited LPS-induced pulmonary neutrophilia with ED50s of 1.1 μg/kg (aqueous suspension) and 2.9 μg/kg (dry powder formulation) and was more potent than an aqueous suspension of the corticosteroid fluticasone propionate (ED50 9.3 μg/kg). Thus, GSK256066 has been demonstrated to have exceptional potency in vitro and in vivo and is being clinically investigated as a treatment for COPD. This article has not been copyedited and formatted. The final version may differ from this version. JPET Fast Forward. Published on January 4, 2011 as DOI: 10.1124/jpet.110.173690 at A PE T Jornals on M ay 9, 2017 jpet.asjournals.org D ow nladed from