Description
E6005 is an inhibitor of phosphodiesterase 4 (PDE4; IC
50 = 2.8 nM). It is selective for PDE4 over PDE1, PDE2, PDE3, and PDE5 with only 46.1, 51.6, 69.4, and 57.4% inhibition, respectively, at 30 μM. It inhibits the production of various cytokines in isolated human lymphocytes and monocytes (IC
50s = 0.49-3.1 nM). Topical application of E6005 (0.003-0.3%) reduces ear thickness in a mouse model of oxazolone-induced skin inflammation, as well as reduces oxazolone-induced scratching in mice. It reduces the severity of skin lesions in a model of mite-induced atopic dermatitis. Topical application of E6005 (0.03%) also inhibits the production of leukotriene B
4 (LTB
4; ) in mouse skin, as well as reduces scratching and cutaneous nerve firing induced by the proteinase-activated receptor 2 (PAR2) agonist SLIGRL-NH
2 in mice.
in vivo
Lotamilast is currently in phase 2 development for patients with mild-to-moderate atopic dermatitis. In mice models, the topical application of Lotamilast produces an immediate antipruritic effect as well as an anti-inflammatory effect with reduced expression of cytokines/adhesion molecules. On the basis of these observed effects, topical RVT-501 ameliorates the appearance of atopic dermatitis-like skin lesions in two types of AD models, hapten- and mite-elicited models, exhibiting inhibitory effects comparable to that of tacrolimus[1]. A single topical application of Lotamilast significantly inhibits spontaneous scratching during 1–2 h after application in mice with chronic dermatitis; the inhibition is partial and similar between 0.01% and 0.03%. Topical application of 0.03% Lotamilast to the rostral back significantly inhibits the increased activity of the cutaneous nerve in mice with chronic dermatitis. The cutaneous concentration of cAMP is significantly decreased in mice with chronic dermatitis, and this decrease is reversed by topical Lotamilast application[2].
References
[1] NAOTO ISHII. Antipruritic effect of the topical phosphodiesterase 4 inhibitor E6005 ameliorates skin lesions in a mouse atopic dermatitis model.[J]. Journal of Pharmacology and Experimental Therapeutics, 2013, 346 1: 105-112. DOI:
10.1124/jpet.113.205542[2] TSUGUNOBU ANDOH Yasushi K. Antipruritic mechanisms of topical E6005, a phosphodiesterase 4 inhibitor: Inhibition of responses to proteinase-activated receptor 2 stimulation mediated by increase in intracellular cyclic AMP[J]. Journal of dermatological science, 2014, 76 3: Pages 206-213. DOI:
10.1016/j.jdermsci.2014.10.005
