Atopic dermatitis (AD) is a chronic inflammatory skin disease. the characterizes of AD are eczematous lesions and intense itching.
The immune activation of AD mainly due to Th2 cytokines (IL4, IL5, IL13) and Th22 (IL22). At the same time, the Th17 cytokines also play a role in more chronic AD. The present topical treatment for AD is the topical application of corticosteroids (TCSs) and topical calcineurin inhibitors (TCIs). The topical treatment offers direct access to targets in the skin with the opportunity of reaching high local skin concentrations. Meanwhile, systemic concentrations maintain low and thereby minimizes adverse effects.
The enzyme phosphodiesterase (PDE) 4 exists in most immune cells. Additionally, it breaks down the secondary messenger cyclic adenosine monophosphate (cAMP). PDE4 inhibitors are able to induce increased levels of cAMP in leukocytes.

In this article, we will introduce a dual-soft PDE4 inhibitor, LEO 39652.

It inhibits PDE isoforms with similar inhibitory effects. The IC50s are 1.2 nM, 1.2 nM, 3.0 nM and 3.8 nM for PDE4A, PDE4B, PDE4C and PDE4D, respectively. Besides, LEO 39652 also inhibits TNF-α with an IC50 value of 6.0 nM.
In a pharmacokinetic analysis, LEO 39652 is inactivated both in blood and liver (dual-soft) while stabled in the skin.
Furthermore, to confirm sufficient stability and distribution in the skin, the female Göttingen minipigs are used to support the selection of clinical formulation. LEO 39652 usage in monoglyceride cream contains concentrations 0.1 and 0.25% (both efficacious doses of 1) at 24, 4, 1, and 0.5 h prior to biopsy sampling.

The biopsy concentrations and dermal PK profile of LEO 39652 show the total drug concentrations 24 h after dosing of 17 μM (0.1%) and 24 μM (0.25%), respectively. As a result, on the basis of these numbers, LEO 39652 achieves full target engagement over 24 h. While metabolism in the pigskin does occur, but metabolites constitute ≤25% of the total drug. this means skin metabolism should not prevent LEO 39652 from achieving an efficacious concentration in the skin.

In conclusion, LEO 39652 is a potent PDK4 inhibitor and can be used for atopic dermatitis research.


[1]. Jens Larsen, et al. J Med Chem. 2020 Dec 10;63(23):14502-14521.

[2]. Stefan Eirefelt, et al. Pharm Res. 2020 Nov 13;37(12):243.