33537 Inhibitory effects of ME3183, a novel phosphodiesterase-4 inhibitor, on stimulants-induced production of proinflammatory cytokines and chemokines in whole blood cell cultures of patients with plaque psoriasis

Abstract

Inhibition of phosphodiesterase-4 (PDE4) has been reported as a therapeutic target for inflammatory diseases. ME3183 is an orally available and selective inhibitor of PDE4, which showed various anti-inflammatory effects in nonclinical studies. We examined the inhibitory effects of ME3183 on stimulants-induced production of proinflammatory cytokines and chemokines in whole blood cell cultures of healthy volunteers and patients with plaque psoriasis (Ps). Tumor necrosis factor alpha (TNF-α), interleukin 17A, interferon-γ, monocyte chemotactic protein-1 and interferon gamma-induced protein-10 were measured in each subject’s whole blood cell cultures stimulated with lipopolysaccharide (LPS) or phytohemagglutinin (PHA) in the presence of ME3183 or apremilast. Correlation between the inhibition of TNF-α production and each clinical parameter of patients were statistically analyzed. ME3183 showed approximately 5- to 40-folds more potent inhibitory activities against production of cytokines than apremilast both in the whole blood cell cultures of Ps patients and healthy subjects. Interestingly, our correlation analysis suggested that high body surface area (%) and long-duration of psoriasis may be associated with the potency (IC50) of ME3183 against TNF-α production. ME3183 showed higher potency than apremilast in the inhibition of proinflammatory cytokines and chemokines production. ME3183 can be a new generation of PDE4 inhibitor with improved therapeutic effect, and the efficacy of ME3183 will be investigated in patients with Ps in the P2a study.