Total synthesis and structure-activity relationship study of pyripyropene A, a potent and selective ACAT2 Inhibitor

• Project/Area Number: 22590011
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Chemical pharmacy
• Research Institution: Kitasato University
• Principal Investigator: NAGAMITSU Tohru 北里大学, 薬学部, 教授 (90300756)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2012: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2011: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2010: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 合成化学 / 創薬化学 / pyripyropene A / ACAT2 / ACAT2阻害剤 / 全合成 / 構造活性相関研究 / 創薬研究 / 新規抗高脂血症薬 / Pyripyropene A / 構造活性相関 / 創薬

Research Abstract

We have achieved a stereocontrolled total synthesis of pyripyropene A (1), a potent ACAT2 inhibitor with high isozyme selectivity. Extension of this chemistry for the structure-activity relationship study successfully produced new A-ring truncated pyripyropene A analogs.

Research Products

• [Journal Article] Synthesis and Structure-Activity Relationship of Pyripyropene A Derivatives as Potent and Selective Acyl-CoA:cholesterol Acyltransferase 2 (ACAT2) Inhibitors: Part 2 (2013)
  • Author(s): Ohtawa Masaki
  • Journal Title: Bioorganic & Medicinal Chemistry Letters Volume: 23 Issue: 9 Pages: 2659-2662
  • DOI: 10.1016/j.bmcl.2013.02.088
  • Peer Reviewed
• [Journal Article] Synthesis and Structure-Activity Relationship of Pyripyropene A Derivatives as Potent and Selective Acyl-CoA:cholesterol Acyltransferase 2 (ACAT2) Inhibitors: Part 1 (2013)
  • Author(s): Ohtawa Masaki
  • Journal Title: Bioorganic & Medicinal Chemistry Letters Volume: 23 Issue: 5 Pages: 1285-1287
  • DOI: 10.1016/j.bmcl.2012.12.099
  • Peer Reviewed
• [Journal Article] Total Synthesis of Pyripyropene A (2011)
  • Author(s): Odani, A.; Ishihara, K.; Ohtawa, M.; Tomoda, H.; Omura, S.; Nagamitsu, T
  • Journal Title: Tetrahedron Volume: Vol. 67, No. 42 Pages: 8159-8203
  • URL: http://dx.doi.org/10.1016/j.tet.2011.06.084
  • Peer Reviewed
• [Journal Article] Total Synthesis of Pyripyropene A (2011)
  • Author(s): Odani Atsuki
  • Journal Title: Tetrahedron Volume: 67 Issue: 42 Pages: 8195-8203
  • DOI: 10.1016/j.tet.2011.06.084
  • Peer Reviewed
• [Presentation] ACAT2 選択的阻害剤pyripyropene A構造簡略型誘導体の合成研究 (2013)
  • Author(s): 寺山富明
  • Organizer: 日本薬学会第133年会
  • Place of Presentation: 横浜
  • Year and Date: 2013-03-29
• [Presentation] ACAT2選択的阻害剤pyripyropene Aの全合成および創薬研究 (2012)
  • Author(s): 大多和正樹
  • Organizer: 第30回白金シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2012-12-18
• [Presentation] Structure-activity relationship of new pyripyropene A derivatives, inhibitors of acyl-CoA:cholesterol acyltranferase 2 (2012)
  • Author(s): Ohtawa M
  • Organizer: 13th Tetrahedron Symposium - Asia Edition
  • Place of Presentation: Taipei, Taiwan
  • Year and Date: 2012-11-28
• [Presentation] Total synthesis of pyripyropene A (2012)
  • Author(s): Nagamitsu T
  • Organizer: 13th Tetrahedron Symposium - Asia Edition
  • Place of Presentation: Taipei, Taiwan
  • Year and Date: 2012-11-28
• [Presentation] 重要疾患に対する化合物ライブラリーの構築に向けた天然物の全合成 (2012)
  • Author(s): 長光亨
  • Organizer: 第29回白金シンポジウム
  • Place of Presentation: 北里大学薬学部(白金)
  • Year and Date: 2012-01-18
• [Presentation] ACAT2 選択的阻害剤pyripyropene Aの形式全合成 (2011)
  • Author(s): 石原雅織
  • Organizer: AKPS集会第7回北里化学シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2011-12-22
• [Presentation] Pyripyropene Aの低分子化誘導体の合成研究 (2011)
  • Author(s): 寺山富明
  • Organizer: AKPS集会 第7回北里化学シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2011-12-22
• [Presentation] ACAT2選択的阻害剤pyripyropene Aの形式全合成 (2011)
  • Author(s): 石原雅織
  • Organizer: 第7回北里化学シンポジウム
  • Place of Presentation: 北里大学薬学部(白金)
  • Year and Date: 2011-12-22
• [Presentation] Pyripyropene Aの低分子化誘導体の合成研究 (2011)
  • Author(s): 寺山富明
  • Organizer: 第7回北里化学シンポジウム
  • Place of Presentation: 北里大学薬学部(白金)
  • Year and Date: 2011-12-22
• [Presentation] Stracture-activity relationship of new pyripyropene A derivatives, inhibitors of acyl-CoA:cholesterole acyltransferase 2, AIMECS II (2011)
  • Author(s): Ohtawa, M
  • Organizer: The 8th AFMC International Medicinal Chemistry Symposium
  • Place of Presentation: Tokyo
  • Year and Date: 2011-12-01
• [Presentation] ACAT2選択的阻害剤pyripyropen Aの構造活性相関ならびに全合成 (2011)
  • Author(s): 大多和正樹
  • Organizer: 第53回天然有機化合物討論会
  • Place of Presentation: 大阪
  • Year and Date: 2011-09-27
• [Presentation] ACAT2 選択的阻害剤pyripyropene Aの形式全合成 (2011)
  • Author(s): 小谷篤輝
  • Organizer: 日本薬学会第131年会
  • Place of Presentation: 静岡
  • Year and Date: 2011-03-30
• [Presentation] Pyripyropene Aの新規低分子誘導体の合成研究 (2011)
  • Author(s): 市田直樹
  • Organizer: 日本薬学会第131年会
  • Place of Presentation: 静岡
  • Year and Date: 2011-03-30
• [Presentation] ACAT2選択的阻害剤pyripropene Aの形式全合成 (2011)
  • Author(s): 長光亨
  • Organizer: 日本薬学会131年会
  • Place of Presentation: ツインメッセ静岡(静岡)
  • Year and Date: 2011-03-30
• [Presentation] Pyripyropenene Aの新規低分子誘導体の合成研究 (2011)
  • Author(s): 長光亨
  • Organizer: 日本薬学会131年会
  • Place of Presentation: ツインメッセ静岡(静岡)
  • Year and Date: 2011-03-30
• [Presentation] ACAT2 選択的阻害剤pyripyropene Aの形式全合成 (2010)
  • Author(s): 小谷篤輝
  • Organizer: 第60回有機合成化学協会関東支部シンポジウム
  • Place of Presentation: 新潟
  • Year and Date: 2010-12-05
• [Presentation] ACAT2選択的阻害剤pyripyropene Aの形式全合成 (2010)
  • Author(s): 長光亨
  • Organizer: 第60回有機合成化学協会関東支部シンポジウム
  • Place of Presentation: 新潟薬科大学新津キャンパス
  • Year and Date: 2010-12-05
• [Presentation] Pyripyropene Aの新規低分子誘導体の合成研究 (2010)
  • Author(s): 市田直樹
  • Organizer: 第29回メディシナルケミストリーシンポジウム
  • Place of Presentation: 京都
  • Year and Date: 2010-11-17
• [Presentation] ACAT2 選択的阻害剤pyripyropene Aの形式全合成 (2010)
  • Author(s): 小谷篤輝
  • Organizer: 第29回メディシナルケミストリーシンポジウム
  • Place of Presentation: 京都
  • Year and Date: 2010-11-17
• [Presentation] ACAT2選択的阻害剤pyripyropene Aの形式全合成 (2010)
  • Author(s): 長光亨
  • Organizer: 第29回メティシナルケミストリーシンポジウム
  • Place of Presentation: 京都テルサ(京都)
  • Year and Date: 2010-11-17
• [Presentation] Pyripyropene Aの新規低分子誘導体の合成研究 (2010)
  • Author(s): 長光亨
  • Organizer: 第29回メティシナルケミストリーシンポジウム
  • Place of Presentation: 京都テルサ(京都)
  • Year and Date: 2010-11-17
• [Presentation] ACAT2 選択的阻害剤pyripyropene Aの形式全合成 (2010)
  • Author(s): 小谷篤輝
  • Organizer: 54回日本薬学会関東支部大会
  • Place of Presentation: 東京
  • Year and Date: 2010-10-02
• [Presentation] Pyripyropene Aの新規低分子誘導体の合成研究 (2010)
  • Author(s): 市田直樹
  • Organizer: 第54回日本薬学会関東支部大会
  • Place of Presentation: 東京
  • Year and Date: 2010-10-02
• [Presentation] ACAT2選択的阻害剤pyripyropene Aの形式全合成 (2010)
  • Author(s): 長光亨
  • Organizer: 第54回日本薬学会関東支部大会
  • Place of Presentation: 東京薬科大学
  • Year and Date: 2010-10-02
• [Presentation] Pyripyropene Aの新規低分子誘導体の合成研究 (2010)
  • Author(s): 長光亨
  • Organizer: 第54回日本薬学会関東支部大会
  • Place of Presentation: 東京薬科大学
  • Year and Date: 2010-10-02
• [Presentation] ACAT2 選択的阻害剤pyripyropene Aの誘導体合成と構造活性相関 (2010)
  • Author(s): 大多和正樹
  • Organizer: 第5回医薬品原料国際展 医薬品化学研究発表大会 アカデミックシンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2010-06-30
• [Presentation] Structure-activity relationship of new pyripyropene A derivatives, inhibitors of acyl-CoA:cholesterol acyltransferase 2 (2010)
  • Author(s): Ohtawa M
  • Organizer: The 21st French-Japanese Symposium on Medicinal and Fine Chemistry
  • Place of Presentation: Kyoto
  • Year and Date: 2010-05-10
• [Presentation] Total synthesis of pyripyropene A
  • Author(s): Nagamitsu Tohru
  • Organizer: 13th Tetrahedron Symposium–Asia Edition
  • Place of Presentation: Taipei, Taiwan
• [Presentation] Structure-activity relationship of new pyripyropene A derivatives, inhibitors of acyl-CoA:cholesterol acyltranferase 2
  • Author(s): Ohtawa Masaki（Nagamitsu Tohru）
  • Organizer: 13th Tetrahedron Symposium–Asia Edition
  • Place of Presentation: Taipei, Taiwan
• [Presentation] ACAT2選択的阻害剤pyripyropene Aの全合成および創薬研究
  • Author(s): 大多和正樹（長光 亨）
  • Organizer: 第30回白金シンポジウム
  • Place of Presentation: 東京
• [Presentation] ACAT2選択的阻害剤pyripyropene A構造簡略型誘導体の合成研究
  • Author(s): 寺山富明（長光 亨）
  • Organizer: 日本薬学会第133年会
  • Place of Presentation: 横浜
• [Remarks]
  • URL: http://www.pharm.kitasato-u.ac.jp/orgsynth/saito/TOP_PAGE.html
• [Remarks] 北里大学薬学部／北里大学大学院薬学研究科 薬品製造化学教室
  • URL: http://www.pharm.kitasato-u.ac.jp/orgsynth/saito/TOP_PAGE.html
• [Remarks]
  • URL: http://www.pharm.kitasato-u.ac.jp/orgsynth/saito/PUBLICATION.html
• [Patent(Industrial Property Rights)] ACAT2阻害活性を示すピリピロペンA構造簡略型誘導体 (2013)
  • Inventor(s): 大多和正樹、大村智、供田洋、長光亨
  • Industrial Property Rights Holder: 大多和正樹、大村智、供田洋、長光亨
  • Industrial Property Number: 2013-012868
  • Filing Date: 2013-01-28
• [Patent(Industrial Property Rights)] ACAT2阻害活性を示す代謝酵素に安定なピリピロペン誘導体 (2011)
  • Inventor(s): 供田洋、長光亨、松田大介、大城太一、大多和正樹、大村智
  • Industrial Property Rights Holder: 供田洋、長光亨、松田大介、大城太一、大多和正樹、大村智
  • Filing Date: 2011-03-25
• [Patent(Industrial Property Rights)] ACAT2阻害活性を示す水酸基含有ピリピロペン誘導体 (2010)
  • Inventor(s): 供田洋、長光亨、松田大介、大城太一、大多和正樹、大村智
  • Industrial Property Rights Holder: 供田洋、長光亨、松田大介、大城太一、大多和正樹、大村智
  • Filing Date: 2010-06-21