Biochem/physiol Actions

GSK256066 is a reversible and cAMP-competitive phosphodiesterase 4 (PDE4) inhibitor that targets all PDE4 subtypes with high affinity (IC50 = 53.7 pM against 2 nM [3H]-rolipram for binding HRBS in rat brain cytosol), potency and selectivity (pIC50 ≥11.31/11.5/11.42/11.94 against PDE4A/B/C/D vs. pIC50 = 5.73/5.92/5.93/5.39/5.28/8.11 against PDE1/2/3/5/6/7 by SPA assays). GSK256066 effectively inhibits LPS-induced TNFA production from human whole blood and isolated PBMCs (pIC50 = 126 and 10 pM, respectively) in vitro and acute pulmonary neutrophilia in rats in vivo (ED50 = 1.1 μg/kg, administered intratracheally 2 hrs priror to LPS). GSK256066 is shown to be more potent than Cilomilast (SB-207499) and Roflumilast in both cell-free and cell-based assays.