GSK356278

720704-34-7

439.53

10 mM in DMSO

Metabolic Enzyme/Protease

GSK356278 is a potent, selective, orally bioavailable and brain-penetrant inhibitor of phosphodiesterase 4 (PDE4), with pIC₅₀s of 8.6, 8.8, and 8.7 for human PDE4A, PDE4B, and PDE4D, respectively. GSK356278 has anti-inflammatory activity, and exhibits anxiolytic and cognition-enhancing effects^[1]. In Vitro: GSK356278 competes with [³H]rolipram for the high affinity rolipram binding site (HARBS) with a pK_i of 8.6 in a competitive filtration-binding assay to the recombinant human PDE4B2B enzyme expressed in yeast membranes^[1].
GSK356278 bounds to the HARBS in rats, mice, marmosets, and ferrets with pK_is of 7.9, 7.8, 8.4, and 8.5, respectively^[1].
GSK356278 inhibits LPS-induced release of TNF-alpha in human whole blood, with a pIC₅₀ of 7.6^[1]. In Vivo: GSK356278 (0.003-30 mg/kg; p.o.) shows anti-inflammatory activity in rodents at exposures that does not induce pica feeding^[1].
GSK356278 (0.1-0.1 mg/kg; p.o.) demonstrates efficacy in a nonhuman primate model of anxiety at exposures that do not induce emesis^[1].
GSK356278 (4 doses at 0.03, 0.1, 0.3, and 1.0 mg/kg for 6 weeks; p.o.) enhances performance in a nonhuman primate object retrieval test^[1]. GSK356278 exhibits oral bioavailability (rat 91%, monkey 23%) and C_max (rat 205, monkey 41 nM) following oral administration (rat 1, monkey 0.2 mg/kg)^[1].
GSK356278 exhibits terminal elimination half-lives (rat 2.2, monkey 1.5 h) due to moderate blood clearance (rat 40, monkey 16 mL/min/kg) combined with volumes of distribution (rat 6.3, monkey 2.1 L/kg) following intravenous administration (rat 1, monkey 0.2 mg/kg)^[1].