Explolation of gamma-secretase modulator based on metabolic nuclear receptor

• Project/Area Number: 23590128
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Okayama University
• Principal Investigator: HIROYUKI MIYACHI 岡山大学, 医歯(薬)学総合研究科, 教授 (20376643)
• Co-Investigator(Kenkyū-buntansha): MATSUNO Kenji 岡山大学, 大学院医歯薬学総合研究科, 准教授 (50433214)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2012: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2011: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: アルツハイマー / PPAR / プロピオン酸 / チアゾリジンジオン / γセクレターゼ / secretase / NOTCH / フェニルプロピオン酸

Research Abstract

In order to create new anti dementia agents, we explored gamma-secretase inhibitors derived from PPAR agonists. The structure-activity relationship was investigated. In addition, we performed photo affinity labelling competition experiment to understand the mechanism(s) of action of the discovered compound, and found that the newly developed compounds binds to different site of plesenilin 1 as compared to the known ligands.

Research Products

• [Journal Article] Design and synthesis of a series ofα-benzyl phenylpropanoic acid-type peroxisome proliferator-activated receptor (PPAR) gamma partial agonists with improved aqueous solubility (2013)
  • Author(s): Ohashi M, Oyama T, Putranto EW, Waku T, Nobusada H, Kataoka K, Matsuno K, Yashiro M, Morikawa K, Huh NH, Miyachi H
  • Journal Title: Bioorg Med Chem Volume: 21(8) Pages: 2319-2332
• [Journal Article] Peroxisome Proliferator-Activated Receptor delta Antagonists Inhibit Hepatitis C Virus RNA Replication (2013)
  • Author(s): Ban S, Ueda Y, Ohashi M, Matsuno K, Ikeda M, Kato N, Miyachi H
  • Journal Title: Bioorg. Med. Chem. Lett Volume: 23(17) Pages: 4774-4778
• [Journal Article] Structure-guideddesign,synthesis and in vitro evaluation of a series of pyrazole-based fatty acid binding protein (FABP) 3 ligands (2013)
  • Author(s): Beniyama Y, Matsuno K, Miyachi H
  • Journal Title: Bioorg. Med. Chem. Lett Volume: 3 Pages: 1662-1666
• [Journal Article] Design and synthesis of a series of a-benzyl phenylpropanoic acid-type peroxisome proliferator-activated receptor (PPAR) gamma partial agonists with improved a queous solubility. (2013)
  • Author(s): Masao Ohashi, et.al.
  • Journal Title: Bioorg. Med Chem. Volume: 21 Issue: 8 Pages: 2319-2332
  • DOI: 10.1016/j.bmc.2013.02.003
  • Peer Reviewed
• [Journal Article] Peroxisome proliferator-activated receptor delta antagonists inhibit hepatitis C virus RNA replication. (2013)
  • Author(s): Ban S, Ueda Y, Ohashi M, Matsuno K, Ikeda M, Kato N, Miyachi H.
  • Journal Title: Bioorg Med Chem Lett. Volume: 23 Issue: 17 Pages: 4774-4778
  • DOI: 10.1016/j.bmcl.2013.07.005
  • Peer Reviewed
• [Journal Article] Structure-guided design, synthesis and in vitro evaluation of a series of pyrazole-based fatty acid binding protein (FABP) 3 ligands. (2013)
  • Author(s): Beniyama Y, Matsuno K, Miyachi H.
  • Journal Title: Bioorg Med Chem Lett. Volume: 23 Issue: 6 Pages: 1662-1666
  • DOI: 10.1016/j.bmcl.2013.01.054
  • Peer Reviewed
• [Journal Article] Design, synthesis and in vitro evaluation of a series ofα-substituted phenylpropanoic acid PPARγagonists to further investigate the stereochemistry-activity relationship (2012)
  • Author(s): Ohashi M, Nakagome I, Kasuga J, Nobusada H, Matsuno K, Makishima M, Hirono S, Hashimoto Y, Miyachi H
  • Journal Title: Bioorg. Med. Chem Volume: 20 Pages: 375-383
• [Journal Article] Design, synthesis and in vitro evaluation of a series of a-substituted phenylpropanoic acid PPARy agonists to further investigate the stereochemistry-activity relationship (2012)
  • Author(s): Masao Ohashi, et.al.
  • Journal Title: Bioorg. Med Chem. Volume: 20 Issue: 21 Pages: 6375-6383
  • DOI: 10.1016/j.bmc.2012.08.061
  • Peer Reviewed
• [Journal Article] Bidirectional fluorescence properties of pyrene-based peroxisome proliferator-activated receptor (PPAR) α/δ dual agonist. (2012)
  • Author(s): Shintaro Ban 他７名
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 20 Issue: 11 Pages: 3460-3464
  • DOI: 10.1016/j.bmc.2012.04.015
  • Peer Reviewed
• [Journal Article] Peroxisome proliferator-activated receptors (PPARs) have multiple binding points (2012)
  • Author(s): Kuwabara N, Oyama T, Tomioka D, Ohashi M, Yanagisawa J, Shimizu T, Miyachi H.
  • Journal Title: J. Med.Chem. Volume: 55 Issue: 2 Pages: 893-902
  • DOI: 10.1021/jm2014293
  • Peer Reviewed
• [Journal Article] Design, Synthesis, and Structural Analysis of Phenylpropanoic Acid-Type PPARγ-Selective Agonists : Discovery of Reversed Stereochemistry-Activity Relationship (2011)
  • Author(s): Ohashi M, Oyama T, Nakagome I, Satoh M, Nishio Y, Nobusada H, Hirono S, Morikawa K, Hashimoto Y, Miyachi H
  • Journal Title: J. Med. Chem Volume: 54 Pages: 331-341
• [Journal Article] Structure-based design, synthesis, and nonalcoholic steatohepatitis (NASH)-preventive effect of phenylpropanoic acid peroxisome proliferator-activated receptor (PPAR)α-selective agonists (2011)
  • Author(s): Ban S, Kasuga J, Nakagome I, Nobusada H, Takayama F, Hirono S, Kawasaki H, Hashimoto Y, Miyachi H
  • Journal Title: Bioorg. Med. Chem Volume: 19 Pages: 3183-3191
• [Presentation] 新規NOTCH-sparingγセクレターゼ阻害剤の創製 (2011)
  • Author(s): 黒住元紀元、西尾淑暢、宮地弘幸、他
  • Organizer: 創薬懇話会2011
  • Place of Presentation: ダイアモンド瀬戸内マリンホテル