Design, Synthesis, and Biological Evaluation of an Orally Bioavailable, Potent, and Selective ROCK2 Inhibitor for Psoriasis Treatment
- J Med Chem. 2023 Nov 23;66(22):15205-15229. doi: 10.1021/acs.jmedchem.3c01297.
- 1. Institute of Marine Biology and Pharmacology, Ocean College, Zhejiang University, Zhoushan 316021, China.
- 2. Key Laboratory of Digestive Pathophysiology of Zhejiang Province, the First Affiliated Hospital of Zhejiang Chinese Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, China.
- 3. Hainan Institute of Zhejiang University, Sanya 572025, China.
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 (A31-35). Notably, A32-35 outperform KD025 in ROCK2/ROCK1 selectivity by up to 216-fold. Among these candidates, A31 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 A31 notably ameliorated symptoms by targeting the IL-23/Th17 axis. Based on these compelling findings, A31 was selected as a highly promising compound for further investigation as a potential treatment for psoriasis.