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제124회 대한화학회 학술발표회, 총회 및 기기전시회 안내 Discovery of Novel β-arrestin-biased S1P1 Agonists for Treatment of Multiple Sclerosis

2019년 8월 30일 16시 43분 02초
MEDI.O-3 이곳을 클릭하시면 발표코드에 대한 설명을 보실 수 있습니다.
목 09시 : 30분
Medicinal Chemistry - Oral Presentation of Young Discovery Chemists
저자 및
WooSeung Son, Hyeon Jeong Kim1, Siwon Kim2, Jong-Hyun Park3, Sang Min Lim2, Ki Duk Park1, Kyu-Sung Jeong, Ae Nim Pae2,*
Department of Chemistry, Yonsei University, Korea
1Convergence Research Center for Dementia, Korea Institute of Science and Technology, Korea
2Korea Institute of Science and Technology, Korea
3Convergence Research Center for Dementia DTC, Korea Institute of Science and Technology, Korea
Multiple sclerosis (MS) is a chronic, progressive autoimmune disease which causes demyelination of the CNS. The non-selective Sphingosine-1-phosphate (S1P) receptor modulator, FTY720, binds to S1P1, 3, 4, 5. In Human clinical trials, it is associated with diverse side effects such as hypertension by S1P3 agonism. 1 Our rationale of developing novel 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. The synthesized compound KKPS0075 showed remarkable in vitro activities (Ca2+ signaling assay, EC50=23 nM, β-arrestin assay, EC50=1.98 nM and Internalization assay, EC50=0.65 nM) with sparing activity against S1P3 receptor. Furthermore, the compound KKPS0073 show β-arrestin biased signaling as S1P1 agonist(Ca2+ signaling assay, EC50=111 nM, β-arrestin assay, EC50=0.17 nM and Internalization assay, EC50=5.04 nM). Optimization of pharmacokinetic properties and in vivo study is ongoing.