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Development of novel anti-atheroscleroic agents

Research Project

Project/Area Number 12557220
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field 医薬分子機能学
Research InstitutionKumamoto University

Principal Investigator

NAKAYAMA Hitoshi  Kumamoto University, Graduate School of Medical and Pharmaceutical Sciences, Professor, 大学院・医学薬学研究部, 教授 (70088863)

Co-Investigator(Kenkyū-buntansha) KUNIYASU Akihiko  Kumamoto University, Graduate School of Medical and Pharmaceutical Sciences, Associate Professor, 大学院・医学薬学研究部, 助教授 (90241348)
MIYAZAKI Akira  Showa University, School of Medicine, Professor, 医学部, 教授 (70253721)
ISHIZUKA Tadao  Kumamoto University, Graduate School of Medical and Pharmaceutical Sciences, Associate Professor, 大学院・医学薬学研究部, 助教授 (60176203)
SANNO-HE Kunio  Mitsui Chemical Co., Institute for Material Sciences, Team Leader, マテリアルサイエンス研究所, 計算科学室長
NISHI Takao  Ohtsuka Pharmaceutical Co., Section of Medical Creation, Team Leader, 徳島第2工場・医薬生産部研究室, 室長
Project Period (FY) 2000 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥12,400,000 (Direct Cost: ¥12,400,000)
Fiscal Year 2002: ¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2001: ¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2000: ¥5,700,000 (Direct Cost: ¥5,700,000)
Keywordssulfonylurea / glibenclamide / macrophage / CD36 / ACAT inhibitors / cholesterol metabolism / scavenger receptors
Research Abstract

We have found that glibendamide, a typical antidiabetic sulfonylurea, inhibits acyl CoA:cholesterol acyllransferase (ACAT) that plays a crucial role to esterify the intracellular free cholesterol and a trigger to form foamed cells in macrophage. In this project we aim to develop novel ACAT inhibitors that are distinct from conventional ones in chemical structures and properties, because the conventional drug candidates of chemically neutral in charge are worried about their adverse effects on adrenal grand. During the passed three years, we organized a team of bioorganic chemist, synthetic organic chemist, molecular pharmacologist, and professionals in in vivo evaluation of drugs, and incomputer-aided drug design. We are succeeded in creating several drug candidates that are eliminated inslin secrition activity and have unique characteristics for ACAT inhibition in term of selective deliverly to taget cells and organs. The compounds are preparing for the patents and we will open the detailed information after the patent issue is completed.

Report

(4 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • Research Products

    (30 results)

All 2003 2002 2001 Other

All Journal Article (12 results) Publications (18 results)

  • [Journal Article] CD36-mediated endocytic uptake of AGE in mouse 3T3-L1 and human subcutaneous adipocytes.2003

    • Author(s)
      A.Kuniyasu, et al.
    • Journal Title

      FEBS Lett. 537

      Pages: 85-90

    • Related Report
      2002 Annual Research Report
  • [Journal Article] Photochemical identification of the binding region for (S)-semotiadil on sodium channels.2003

    • Author(s)
      H.Yoshikawa, et al.
    • Journal Title

      Heterocycles 59(2)

      Pages: 613-622

    • Related Report
      2002 Annual Research Report
  • [Journal Article] Scavenger receptors that recognize advanced glycation end products2002

    • Author(s)
      A.Miyazaki, et al.
    • Journal Title

      Trends Cardiovasc.Med. 12(6)

      Pages: 258-262

    • Related Report
      2002 Annual Research Report
  • [Journal Article] Efficient identification of photolabelled amino acids by immuno-purification and mass spectrometry2002

    • Author(s)
      K.Kawahara, et al.
    • Journal Title

      Biochem.J. 363(2)

      Pages: 223-232

    • Related Report
      2002 Annual Research Report
  • [Journal Article] Adipocytes recognize and degrade oxidized LDL through CD362002

    • Author(s)
      A.Kuniyasu, et al.
    • Journal Title

      Biochem.Biophys.Res.Commun. 295(2)

      Pages: 319-323

    • Related Report
      2002 Annual Research Report
  • [Journal Article] Efficient identification of photolabeled amino acids by immuno-purification and mass spectrometry.2002

    • Author(s)
      K.Kawahara, et al.
    • Journal Title

      Biochem.J. (in press)

    • Related Report
      2001 Annual Research Report
  • [Journal Article] Induction of CHOP and apoptosis by nitric oxide in p53-deficient microglial cells.2001

    • Author(s)
      K.Kawahara, et al.
    • Journal Title

      FEBS Lett. 506(2)

      Pages: 135-139

    • Related Report
      2002 Annual Research Report
  • [Journal Article] Novel wasp toxin discriminates between neuronal and cardiac sodium channels.2001

    • Author(s)
      E.Kinoshita, et al.
    • Journal Title

      Mol.Pharmacol. 59

      Pages: 1457-1463

    • Related Report
      2001 Annual Research Report
  • [Journal Article] Asymmetric arrangement of auxiliary subunit of skeletal muscle L-type Ca^<2+> channel.2001

    • Author(s)
      K.Murata, et al.
    • Journal Title

      Biochem.Biophys.Res.Commun. 282

      Pages: 284-291

    • Related Report
      2001 Annual Research Report
  • [Journal Article] CD36 functions as a receptor for advanced glycatioin end products.2001

    • Author(s)
      N.Ohgami, et al.
    • Journal Title

      Ann.N.Y.Acad.Sci. 947

      Pages: 350-355

    • Related Report
      2001 Annual Research Report
  • [Journal Article] Induction of CHOP and apoptosis by nitric oxide in p53-defecient microgrial cells.2001

    • Author(s)
      K.Kawahara, et al.
    • Journal Title

      FEBS Lett. 506

      Pages: 135-139

    • Related Report
      2001 Annual Research Report
  • [Journal Article] Co-induction of argininosuccinate-synthetase, CAT-2, and NOS in activated microglial cells.2001

    • Author(s)
      K.Kawahara, et al.
    • Journal Title

      Mol.Brain Res. 90

      Pages: 165-173

    • Related Report
      2001 Annual Research Report
  • [Publications] A.Kuniyasu, et al.: "CD36-mediated endocytic uptake of AGE in mouse 3T3-L1 and human subcutaneous adipocytes"FEBS Lett.. 537. 85-90 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] H.Yoshikawa, et al.: "Photochemical identification of the binding region for (S)-semotiadil on sodium channels"Heterocycles. 59(2). 613-622 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] A.Miyazaki, et al.: "Scavenger receptors that recognize advanced glycation end products"Trends Cardiovasc.Med.. 12(6). 258-262 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] K.Kawahara, et al.: "Efficient identification of photolabeled amino acid by immuno-purification and mass spectrometry"Biochem. J.. 363(2). 223-232 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] A.Kuniyasu, et al.: "Adipocytes recognize and degrade oxidized LDL through CD36"Biochem.Biophys.Res.Commun. 295(2). 319-323 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] K.Kawahara, et al.: "Induction of CHOP and apoptosis by nitric oxide in p53-deficient microglial cells"FEBS Lett.. 506(2). 135-139 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kuniyasu, et al.: "CD36-mediated endocytic uptake of AGE in mouse 3T3-L1 and human subcutaneous adipocytes."FEBS. Lett.. 537. 85-90 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] H. Yoshikawa, et al.: "Photochemical identification of the binding region for (s)-semotiadil on sodium channels."Heterocycles. 59(2). 613-622 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] A. Miyazaki, et al.: "Scavenger receptors that recognize advanced glycation end products."Trends Canliovasc. Med.. 12(6). 258-262 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] K. Kawahara, et al.: "Efficient identification of photolabeled amino acids by Immuno-purification and mass spectrometry."Biochem. J.. 363(39). 223-232 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] A. Kuniyasu, et al.: "Adipocytes recognize and degrade oxidized LDL through CD36."Biochem. Biophys. Res. Commun.. 295(2). 319-323 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] K. Kawahara, et al.: "Induction of CHOP and apoptosis by nitric oxide in P53-deflcient microglial cells."FEBS Lett.. 506(2). 135-139 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] H,K,Motoike et al.: "A region in IVS5 of the human cardiac L-type calcium channel is required for the use-dependent block"J.Biol.Chem.. 274(14). 9409-9420 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] A.Kuniyasu et al.: "A new scorpion toxin (BmK-PL) stimulate Ca^<2+>-release channel activity of the sketetal-muscle nyanodine receptor"Biochem.J.. 339. 343-350 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] K.Furuta et al.: "[^<35>S] S-[5-(4-brenzoylphenyl) pentyl] glutathione : A versatile radioligand targeting GS-X pump"Bioorg.Med.Chem.Lett.. 9. 2661-2666 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] V.T.G.Chuang et al.: "Helix 6 of subdomain IIIA of HSA is the region primarily photolabeled by ketoprofen"Biochim.Biophys.Acta. 1434. 18-30 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] N.Ohgami et al.: "Glibenclamide acts as an inhibitor of acyl-CoA : cholesterol acyltransferase enzyme"Biochem.Biophys.Res.Commun.. 277. 417-422 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] N.Ohgami et al.: "CD36, a member of the class B scavenger receptor family, as a receptor for advanced glycation end products"J.Biol.Chem.. 276(5). 3195-3202 (2001)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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