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

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

  • J Med Chem. 2022 Feb 24;65(4):3539-3562. doi: 10.1021/acs.jmedchem.1c01979.
Sun Jun Park 1 2 3,  Seul Ki Yeon 1,  Yoowon Kim 1 4,  Hyeon Jeong Kim 1 4,  Siwon Kim 1 2,  Jushin Kim 1 4,  Ji Won Choi 1,  Byungeun Kim 1 2,  Elijah Hwejin Lee 1 2,  Rium Kim 1 2,  Seon Hee Seo 1,  Jaeick Lee 5,  Jun Woo Kim 6,  Ha-Yeon Lee 6,  Hayoung Hwang 6,  Yong-Sun Bahn 4,  Eunji Cheong 4,  Jong-Hyun Park 1 2,  Ki Duk Park 1 2
Affiliations

Affiliations

  • 1 Convergence Research Center for Diagnosis, Treatment & Care System of Dementia, Korea Institute of Science & Technology (KIST), Seoul 02792, Republic of Korea.
  • 2 Division of Bio-Med Science & Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea.
  • 3 Cureverse Co., Ltd., KIST, 1st Floor, H2 Building, 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, KIST, Seoul 02792, Republic of Korea.
  • 6 New Drug Development Center, Daegu Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Republic of Korea.
PMID: 35077170 DOI: 10.1021/acs.jmedchem.1c01979
Abstract

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 S1P1 agonist 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.

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