Lee, Chang Yong Gotina, Lizaveta Kim, Jushin Kim, Jaehwan Ahn, Jee Yun Son, Woo Seung Seo, Seon Hee Park, Jiwoo Kang, Minsik Lee, Jaeick Lee, Jae Yeol Park, Ki Duk Lim, Sang Min Park, Jong-Hyun Pae, Ae Nim 2025-09-22T02:01:35Z 2025-09-22T02:01:35Z 2025-09-16 2025-09 0022-2623 https://pubs.kist.re.kr/handle/201004/153202 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 beta-arrestin biased S1P1 agonists with reduced G-protein activity using a pharmacophore-based approach. Among them, compound 28 showed 4.51-fold beta-arrestin bias relative to fingolimod: (EC50(G-protein)-12.7 nM and EC50(beta-arrestin)-3.23 nM) and strong S1P1 selectivity and favorable drug-like properties. Docking studies suggested its beta-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 beta-arrestin biased S1P1 agonist with effective immunomodulatory activity and improved safety, offering a promising MS therapeutic candidate. English American Chemical Society Discovery of Novel β-Arrestin Biased Sphingosine-1-Phosphate-1 Receptor Agonists for the Treatment of Multiple Sclerosis Article 10.1021/acs.jmedchem.5c00859 1 Journal of Medicinal Chemistry, v.68, no.17, pp.18289 - 18313 Journal of Medicinal Chemistry 68 17 18289 18313 N scie scopus 001556476500001 Chemistry, Medicinal Pharmacology & Pharmacy Article MU-OPIOID RECEPTOR HEART-RATE PERTUSSIS TOXIN PROTEIN S1P(1) FINGOLIMOD MODULATOR POTENT LIGAND SAFETY