Discovery of Novel Selective Dual Agonists Targeting S1PR1 and S1PR5 for the Treatment of Inflammatory Bowel Disease.

Sphingosine-1-phosphate (S1P) receptor agonists have emerged as promising therapeutics for autoimmune diseases, due to their crucial roles in regulating lymphocyte migration, differentiation, and cytokine secretion. Here, a series of novel 3-(naphthalene-1-yl)-1,2,4-oxadiazol derivatives are designed and synthesized as orally bioavailable, selective dual agonists of S1PR1 and S1PR5. Compounds 19 and 37 were identified, exhibiting excellent in vitro agonistic activity and more than 1000-fold selectivity over S1PR2, S1PR3, and S1PR4. Neither compound 19 and 37 displayed detectable agonistic activity toward S1PR3, they demonstrated favorable pharmacokinetic properties and, in contrast to FTY720, showed minimal impact on heart rate in mice. In a dextran sodium sulfate-induced mouse model of inflammatory bowel disease (IBD), compounds 19 and 37 significantly alleviated colitis pathology. Their mechanism of action was further confirmed through S1PR1-dependent inhibition of T cell migration. Collectively, these findings identify compounds 19 and 37 as promising lead candidates for the treatment of IBD.