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.