Discovery of Novel β-Arrestin Biased Sphingosine-1-Phosphate-1 Receptor Agonists for the Treatment of Multiple Sclerosis

Fingolimod, the first nonselective S1P1 modulator for multiple sclerosis (MS), is effective but linked to cardiovascular side effects. To improve the drug safety profile, we developed β-arrestin biased S1P1 agonists with reduced G-protein activity using a pharmacophore-based approach. Among them, compound 28 showed 4.51-fold β-arrestin bias relative to fingolimod: (EC50(G-protein)─12.7 nM and EC50(β-arrestin)─3.23 nM) and strong S1P1 selectivity and favorable drug-like properties. Docking studies suggested its β-arrestin bias is due to weaker interactions with TM3 (especially R120) and stronger TM7 interactions. During in vivo studies, compound 28 reduced peripheral lymphocyte counts to 24.4% of baseline and significantly improved the clinical scores in preventative and therapeutic experimental autoimmune encephalomyelitis mouse models. Cardiovascular safety was confirmed using human induced pluripotent stem cell-derived cardiomyocytes. These results highlight compound 28 as the first β-arrestin biased S1P1 agonist with effective immunomodulatory activity and improved safety, offering a promising MS therapeutic candidate.