Difamilast

Difamilast is an inhibitor of phosphodiesterase 4 (PDE4).¹ It is selective for the PDE4 isoforms PDE4A, PDE4B, PDE4C, and PDE4D (IC₅₀s = 0.0832, 0.0112, 0.2493 and 0.0738 µM, respectively) over PDE5A and PDE10A (IC₅₀s = 4.793 and 1.4346 µM, respectively) and eight other PDEs (IC₅₀s = >10 µM for all). Difamilast (0.01-10 µM) increases intracellular cAMP levels in U937 cells. It inhibits LPS-induced increases in TNF-α secretion from isolated human and mouse peripheral blood mononuclear cells (PBMCs; IC₅₀s = 19 and 3.5 nM, respectively). Topical application of difamilast (3% w/v) decreases ear thickness and CD3⁺ T cell, eosinophil, and neutrophil lesion infiltrates in a mouse model of 2,4,6-trinitrochlorobenzene-induced chronic allergic contact dermatitis. Formulations containing difamilast have been used in the treatment of atopic dermatitis.

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1. Hiyama, H., Arichika, N., Okada, M., et al. Pharmacological profile of difamilast, a novel selective phosphodiesterase 4 inhibitor, for topical treatment of atopic dermatitis. J. Pharmacol. Exp. Ther. 386(1), 45-55 (2023).