123rd General Meeting of the KCS

Type Poster Presentation
Area Medicinal Chemistry
Room No. Exhibition Hall 2
Time 4월 18일 (목요일) 11:00~12:30
Code MEDI.P-393
Subject Development of Potent β-Arrestin-biased S1P₁ Agonist for Treatment of Multiple Sclerosis
Authors Jee yun Ahn, WooSeung Son1, Kyu-Sung Jeong1, Jong-Hyun Park2, Ki Duk Park3, Sang Min Lim4, Ae Nim Pae4,*
Department of Biotechnology, Yonsei University, Korea
1Department of Chemistry, Yonsei University, Korea
2Convergence Research Center for Dementia DTC, Korea Institute of Science and Technology, Korea
3Convergence Research Center for Dementia, Korea Institute of Science and Technology, Korea
4Convergence Research Center For Diagnosis, Treatment and Care System of Dementia, Korea
Abstract Multiple sclerosis (MS) is a T-cell mediated autoimmune disease of the CNS. Fingolimod is the first FDA-approved drug for relapsing MS. In Human clinical trials, it is associated with side effects such as hypertension by non-selective S1P1,3,4,5 receptors agonism.1 Our reason for developing potent and selective S1P1 receptor agonist is to be lower the circulating lymphocytes more efficiently by internalization of S1P1 on lymphocyte.2 We designed and synthesized S1P1 receptor agonists with selectivity against S1P3 receptor via in silico docking study on S1P1 receptor crystal structure. Among synthesized compounds, S38 showed remarkable in vitro activities (Ca2+ signaling assay, EC50= 35 nM, β-arrestin assay, EC50= 0.2 nM and internalization assay, EC50= 2.8 nM) with sparing activity against S1P3 receptor. Furthermore, the compound S21 exhibited β-arrestin biased signaling as S1P1 agonist (Ca2+ signaling assay, EC50= 1.86 μM, β-arrestin assay, EC50= 8.9 nM and internalization assay, EC50=32 nM). The selected compounds, S21, S38 and S40, are being performed peripheral lymphocyte counting assays. The optimization is now in progress on enhancing potency and pharmacokinetic properties to synthesize novel S1P1 agonist.
E-mail 118024@kist.re.kr