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-400
Subject Development of Novel biased agonists against S1P1 receptor for Treatment of Multiple Sclerosis
Authors Sun Jun Park, Ki Duk Park*
Convergence Research Center for DTC, Korea Institute of Science and Technology, Korea
Abstract The sphingosine-1-phosphate (S1P) receptors are the initial lipid G protein-coupled receptors (GPCRs) that are divided into five subtypes; S1P1, S1P2, S1P3, S1P4, and S1P5. In particular, targeting S1P1 with the endogenous ligand, S1P, has shown substantial efficacy in treatment of multiple sclerosis (MS) since it promotes egress of lymphocytes from lymph nodes. The S1P receptor agonist has been shown to induce receptor down-regulation from the cell surface, suggesting that it acts as a functional antagonist of S1P1 to block lymphocyte egress by internalization of the receptor. In this study, we synthesized a series of chemical derivatives to deduce a potent lead compound and evaluated their biological activities and selectivity using a set of complementary assays such as Ca++ flux, cAMP assay, β-arrestin recruitment, and S1P1 receptor internalization. Among the synthesized compounds, KDS1059 exhibited potent activities on β-arrestin recruitment and S1P1 receptor internalization with an EC50 of 180 nM and 10 nM, respectively, whereas it was slightly active (EC50=1.72 M) on Ca++ assay indicating that KDS1059 is a biased agonist. As a continuation of these efforts, we replaced the core part of KDS1059 and we synthesized the KDS8000 series compounds. Among them, KDS8007 has a marvelous efficacy. KDS8007 exhibited potent activities on β-arrestin recruitment and Ca++ assay with an EC50 of 0.37 nM and 96.5 nM, respectively, KDS8007 has approximately 30-fold β-arrestin recruitment than KDS1059. Additionally we are still working on this study. References Birker-Robaczewska, M. etc., al. Mol Pharmacol. 2018, 93, 109-118. Cohen, J. etc., al. Ann Neurol. 2011, 69, 759-777. Marsolais, D. etc., al. Nat Rev. 2009, 8, 297-307.
E-mail h18502@kist.re.kr