Development of a selective S1P1 receptor agonist,Syl930, as a potential therapeutic agent for autoimmune encephalitis

Sphingosine-1-phosphate receptor subtype 1 (S1P₁) is essential for lymphocyte egress from secondary lymphoid organs and is a validated drug target for the treatment of autoimmune disorders. However, during the preclinical and clinical trials of S1P₁ modulators, the undesired activation of S1P₃, a subtype of sphingosine 1-phosphate (S1P) receptors family, by S1P₁ modulators often results in bradycardia in patients. Thus, we designed and synthesized a new series of selective S1P₁ agonists. One of them, Syl930 (the prodrug), is preference to activate S1P₁ but not S1P₃. In this study, we further investigated the therapeutic potential of Syl930 on an experimental autoimmune encephalomyelitis (EAE) model in Lewis rats. We found that Syl930 can activate and internalize S1P₁ receptors and effectively decreased the periphery blood lymphocytes (PBL) in SD rats, and subsequently rendered PBL insensitive to egress signal from secondary lymphoid organs (SLO). Intriguingly, the treatment of Syl930 did not bring any side effect on heart rate of the tested rats. Furthermore, the suppressed PBL caused by Syl930 was able to recover within 3 days after the last dose of treatment, which is correlated to the relatively short elimination half-life of Syl930. In the rat EAE model, therapeutic treatment with Syl930 significantly inhibited the progression of EAE and EAE-associated histological changes in brain and spinal cord of Lewis rats. These results illustrate that, as a selective S1P₁ agonist, Syl930 exhibits a profound and rapidly reversible suppression of lymphocyte trafficking and it has the potential to serve as a therapeutic agent for autoimmune encephalitis.