121st General Meeting of the KCS

Type Poster Presentation
Area Medicinal Chemistry
Room No. Event Hall
Time 4월 19일 (목요일) 11:00~12:30
Code MEDI.P-577
Subject Development of Selective S1P1/5 Receptor Agonists for Treatment of Multiple Sclerosis
Authors Eun Ji Cha, Jaekyun Lee1, Du-Jong Baek, SANG MIN LIM1, Sun-Joon Min2, Yong Seo Cho1,*
Department of Chemistry, Sangmyung University, Korea
1Center for Neuromedicine, Korea Institute of Science and Technology, Korea
2Dept of Chemical & Molecular Eng/Applied Chemistry, Hanyang University, Korea
Abstract Multiple Sclerosis(MS) is an neurodegenerative autoimmune disorder of the central nervous system. The FDA-approved Fingolimod is the first oral drug for relapsing forms of MS. Following phosphorylation in vivo, an active form of fingolimod, acts as a sphingosine 1-phosphate(S1P) receptor modulator, binding with high affinity to S1P receptors (S1P1,3~5). Although it shows high efficacy for treatment of MS, but the non-selective activity of this compound for S1PR3 causes serious side effects such as bradycardia. In this study, we have designed a new series of S1P1 and S1P5 receptor agonists on the basis of the structure of ono-4641 and A-971432. The preliminary in vitro evaluation of the synthesized compounds using calcium mobilization assay showed that their agonistic effects agonist S1P1 and S1P5 are comparable to those of other reported agonist ligands. In addition, we performed β-arrestin internalization and recruitment experiments of hit compounds to verify their β-arrestin dependent signaling pathway. Indeed, KKSM08024 represented 98% and 51% activation values at the concentration of 10μM respectively agonist S1P1 and S1P5 receptor. EC50 value of KKSM08024 was 0.157±0.016μM, which is comparable to that of BAF312 (0.103±0.009 μM), a second generation MS drug developed by Norvatis. Further evaluation and synthesis of these compounds regarding selectivity of S1P1 and S1P5 will be presented in the presentation.
E-mail ijnueahc@naver.com