Design, synthesis and exploration of cyclic imides as PDE4 inhibitors in psoriasis

Psoriasis is a chronic inflammatory skin disorder for which effective oral therapies remain inadequate. Selectively targeting PDE4B has attracted interest as a promising therapeutic target because it modulates inflammatory pathways and offers a more favorable safety profile compared to non-selective PDE4 inhibitors. In this study, we report the design and synthesis of twenty cyclic imide-based derivatives as PDE4 inhibitors. Among the synthesized derivatives, compounds 1a, 2g, and 2k demonstrated promising PDE4B inhibitory activity, exhibiting >50% inhibition at 1 μM and IC₅₀ values of 0.493, 3.997, and 0.226 μM, respectively. Additionally, compound 2k significantly suppressed the induction of TNF-α in HEK-293 cells, indicating anti-inflammatory potential with an IC₅₀ value of 3.39 μM. Molecular docking and interaction analyses showed that compound 2k interacts with the Q pocket making a glutamate switch (GLN-443) and π-clamp (PHE-446). The studies also indicate that compound 2k binds with the CR3 region of the PDE4B active site through key interactions with LEU-674 and LYS-677, further stabilized by coordination with Zn²⁺ and Mg²⁺ ions. DFT calculations showed favorable electronic properties and compatibility of compound 2k with PDE4B. Binding free energy analyses and MD simulations performed over 100 ns collectively indicated the enhanced stability of compound 2k with PDE4B relative to PDE4D. MD simulation results for the compounds 1a, 2g, and 2k were in good agreement with the observed in vitro inhibitory profiles. Overall, these findings highlight compound 2k as a compelling candidate for further evaluation in psoriasis models.