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

Sun Jun Park, Seul Ki Yeon, Yoowon Kim, Hyeon Jeong Kim, Siwon Kim, Jushin Kim, Ji Won Choi, Byungeun Kim, Elijah Hwejin Lee, Rium Kim, Seon Hee Seo, Jaeick Lee, Jun Woo Kim, Ha Yeon Lee, Hayoung Hwang, Yong Sun Bahn, Eunji Cheong, Jong Hyun Park, Ki Duk Park

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)


The sphingosine-1-phosphate-1 (S1P1) receptor agonists have great potential for the treatment of multiple sclerosis (MS) because they can inhibit lymphocyte egress through receptor internalization. We designed and synthesized triazole and isoxazoline derivatives to discover a novel S1P1agonist for MS treatment. Of the two scaffolds, the isoxazoline derivative was determined to have excellent in vitro efficacy and drug-like properties. Among them, compound 21l was found to have superior drug-like properties as well as excellent in vitro efficacies (EC50= 7.03 nM in β-arrestin recruitment and EC50= 11.8 nM in internalization). We also confirmed that 21l effectively inhibited lymphocyte egress in the peripheral lymphocyte count test and significantly improved the clinical score in the experimental autoimmune encephalitis MS mouse model.

Original languageEnglish
Pages (from-to)3539-3562
Number of pages24
JournalJournal of Medicinal Chemistry
Issue number4
Publication statusPublished - 2022 Feb 24

Bibliographical note

Funding Information:
This study was supported by the National Research Foundation of Korea (NRF-2018M3A9C8016849) and the Korea Institute of Science and Technology (KIST) Institutional Program (2E31522).

Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery


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