Design, Synthesis, and Biological Evaluation of an Orally Bioavailable, Potent, and Selective ROCK2 Inhibitor for Psoriasis Treatment

Abstract

Psoriasis, a prevalent chronic skin disorder, remains a significant therapeutic obstacle. This study centers on rho-associated coiled-coil-containing kinase2 (ROCK2) as an advantageous target for treating psoriasis and identifies five potent and selective ROCK2 inhibitors (<b>A31</b>-<b>35</b>). Notably, <b>A32</b>-<b>35</b> outperform KD025 in ROCK2/ROCK1 selectivity by up to 216-fold. Among these candidates, <b>A31</b> emerged as an exceedingly promising molecule, showcasing remarkable inhibitory potency (IC₅₀ = 3.7 ± 0.8 nM), 19-fold ROCK2/ROCK1 selectivity, and favorable pharmacokinetics. Insights from the binding mode study further underscored the pivotal role of interactions with Phe103 on the P-loop in determining the selectivity between ROCK1 and ROCK2. In an imiquimod-induced psoriasis-like mouse model, oral administration of <b>A31</b> notably ameliorated symptoms by targeting the IL-23/Th17 axis. Based on these compelling findings, <b>A31</b> was selected as a highly promising compound for further investigation as a potential treatment for psoriasis.