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

Fingolimod, the first nonselective S1P 1 modulator for multiple sclerosis (MS), is effective but linked to cardiovascular side effects. To improve the drug safety profile, we developed β-arrestin biased S1P 1 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: (EC 50(G‑protein) 12.7 nM and EC 50(β‑arrestin) 3.23 nM) and strong S1P 1 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 S1P 1 agonist with effective immunomodulatory activity and improved safety, offering a promising MS therapeutic candidate.