Abstract

Sphingosine-1-phosphate receptor 1 is a clinically validated therapeutic target for ulcerative colitis. Substantial clinical evidence indicates that highly selective S1PR3-sparing S1PR1 agonists exhibit improved safety, making selectivity enhancement crucial in drug development. We report the rational design and synthesis of 3-aryl-5-bisaryl-1,2,4-oxadiazole derivatives as novel S1PR1 agonists. Among them, TYY-31 displayed single-digit picomolar activity against S1PR1 (EC50 = 1.13 pM) with minimal activity against S1PR2/3/5 (EC50 > 10 μM) and over 30,000-fold selectivity for S1PR1 compared to S1PR4. TYY-31 efficiently induced S1PR1 internalization (EC50 = 0.73 nM) and blocked receptor recycling. Moreover, TYY-31 demonstrates outstanding pharmacokinetic properties. In vivo, TYY-31 effectively ameliorating dextran sulfate sodium-induced colitis in mice at a dose of 0.3 mg/kg, comparable to Ozanimod (1 mg/kg). Additionally, TYY-31 demonstrated excellent cardiac safety characteristics in zebrafish-based assays. These findings highlight TYY-31 as a highly selective and potent S1PR1 agonist with promising potential as a candidate drug for UC treatment.