Discovery and SAR study of highly selective and potent 1,2,4-oxadiazole-based S1PR1 agonists

Sphingosine-1-phosphate receptor 1 (S1PR1) is a validated therapeutic target for immune-mediated diseases such as multiple sclerosis and ulcerative colitis, owing to its critical role in regulating of lymphocyte migration. However, the clinical utility of current S1PR1 agonists is often limited by cardiovascular adverse effects, particularly dose-dependent bradycardia. Enhancing receptor subtype selectivity represents a promising strategy to mitigate these risks. Herein, we describe the discovery and optimization of a novel series of 1,2,4-oxadiazole-based S1PR1 agonists. Among these, Y18 exhibited potent agonistic activity toward S1PR1 (EC₅₀ = 0.98 nM) with >10,000-fold selectivity over S1PR2, S1PR3, and S1PR5, as well as 109-fold selectivity over S1PR4. Functional studies demonstrated that Y18 efficiently induced S1PR1 internalization, blocked receptor recycling, and activated downstream ERK1/2 phosphorylation. The excellent selectivity across the S1PR family, along with its functional profile, supports Y18 as a promising candidate for S1PR1-targeted therapeutics.