Explolation of gamma-secretase modulator based on metabolic nuclear receptor

2013 Fiscal Year Final Research Report

• 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
• 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

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, 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 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