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제124회 대한화학회 학술발표회, 총회 및 기기전시회 안내 Development of Novel biased agonists against S1P1 receptor for Treatment of Multiple Sclerosis

등록일
2019년 8월 27일 17시 18분 15초
접수번호
1652
발표코드
MEDI.P-275 이곳을 클릭하시면 발표코드에 대한 설명을 보실 수 있습니다.
발표시간
10월 17일 (목요일) 11:00~12:30
발표형식
포스터
발표분야
Medicinal Chemistry
저자 및
공동저자
Sun Jun Park, Ki Duk Park1,*
Department of Chemistry, Korea Institute of Science and Technology, Korea
1Convergence Research Center for Dementia, Korea Institute of Science and Technology, Korea
The sphingosine-1-phosphate receptors are the initial lipid G protein-coupled receptors 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 derivatives and evaluated their biological activities and selectivity using a set of complementary assays such as Ca++ flux, 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 182 nM and 12 nM, respectively, whereas it was slightly active (EC50=1720 nM) on Ca++ assay indicating that KDS1059 is a biased agonist. To optimize biased agonism, we synthesized KDS8000 series compounds by replacing the core part of KDS1059. Among the optimized compounds, KDS8024 exhibited most potent activities on β-arrestin recruitment and internalization with an EC50 of 0.23 nM and 0.05 nM, respectively. Peripheral lymphocyte count (PLC) assay was performed using blood samples from rats treated with KDS8000 series. KDS8007, KDS8022, KDS8024 reduced the number of peripheral lymphocyte which is similar effects to FTY720/fingolimod/GilenyaⓇ. Furthermore, experimental autoimmune encephalitis(EAE) model experiments were conducted and KDS8024 effectively lowered the score of EAE mice. Taken together, KDS 8024 is most promising candidate with excellent biased agonism for treatment of MS. 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.

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