Design, Synthesis, and Biological Evaluation of Novel Arylethanone Oxime Ether Derivatives as Potent S1PR1 Agonists for Ulcerative Colitis Therapy.

S1PR1 is a clinically validated key therapeutic target for ulcerative colitis (UC), but approved S1PR1 agonists universally suffer from the core drawback of S1PR3-mediated cardiotoxicity. Herein, we designed and synthesized multiple novel arylethanone oxime ethers-based S1PR1 agonists. Among them, compound 13d exhibited potent in vitro agonistic activity toward S1PR1 (EC50 = 26 pM, cAMP assay), with no significant activity toward S1PR3 (EC50 > 10 μM, calcium flux assay). More importantly, this compound demonstrated favorable drug-like properties (97.2% oral bioavailability in mice). Mechanistically, 13d induced S1PR1 receptor internalization in a time- and concentration-dependent manner, consistent with the established mechanism of S1PR1-mediated lymphocyte sequestration. In vivo studies further revealed that 13d exhibits favorable cardiac safety and dose-dependently decreases peripheral blood lymphocyte counts. In the DSS-induced acute UC mouse model, 13d at 1 mg/kg/day significantly decreased the disease activity index. In conclusion, this study provides a promising new candidate for UC therapy.