2. Academic Validation
  3. Discovery of Novel β-Arrestin Biased Sphingosine-1-Phosphate-1 Receptor Agonists for the Treatment of Multiple Sclerosis

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

  • J Med Chem. 2025 Sep 11;68(17):18289-18313. doi: 10.1021/acs.jmedchem.5c00859.
Chang Yong Lee 1 2,  Lizaveta Gotina 1 3,  Jushin Kim 1 4,  Jaehwan Kim 1 3,  Jee Yun Ahn 1,  Woo Seung Son 1,  Seon Hee Seo 1,  Jiwoo Park 1,  Minsik Kang 5,  Jaeick Lee 5,  Jae Yeol Lee 6,  Ki Duk Park 1 3,  Sang Min Lim 1 3,  Jong-Hyun Park 1 3,  Ae Nim Pae 1 3
Affiliations

Affiliations

  • 1 Center for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology, 5, Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea.
  • 2 KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 20447, Korea.
  • 3 Division of Bio-Medical Science & Technology, KIST School, University of Science and Technology, 5, Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea.
  • 4 Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea.
  • 5 Doping Control Center, Research Resources Division, Korea Institute of Science and Technology, 5, Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea.
  • 6 Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul 02447, Republic of Korea.
PMID: 40853740 DOI: 10.1021/acs.jmedchem.5c00859
Abstract

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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z