Design, synthesis and biological evaluation of pyripyropene A truncated analogs as ACAT2 selective inhibitor

• Project/Area Number: 25460152
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Kitasato University
• Principal Investigator: Ohtawa Masaki 北里大学, 薬学部, 講師 (70453503)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 創薬化学 / 構造活性相関 / ACAT / 有機合成化学 / 天然物化学 / 合成化学 / ACAT2選択的阻害剤 / 天然有機化合物 / 化合物設計

Outline of Final Research Achievements

Pyripyropene A, isolated from the culture broth of Aspergillus fumigatus FO-1289, is currently the only compound known to strongly and selectivity inhibit the acyl-CoA: cholesterol acyltransferase 2 (ACAT2) isozyme. To assist the development of new cholesterol-lowering or anti-atherosclerotic agents, we designed new A-ring truncated pyripyropene A analogs. We report here our successful synthesis of truncated analogs via a stereoselective intramolecular Michael cyclization method, and the construction of a 6-pyridyl-alfa-pyrone moiety.

Research Products

• [Journal Article] Design, synthesis and biological evaluation of air-stable nafuredin-γ analogs as complex II inhibitors. (2015)
  • Author(s): Ohtawa, M.; Matsunaga, M.; Fukunaga, K.; Shimizu, R.; Shimizu, E.; Arima, S.; Ohmori, J.; Kita, K.; Shiomi, K.; Omura, S.; Nagamitsu. T.
  • Journal Title: Bioorg. Med. Chem. Volume: 23 Issue: 5 Pages: 932-943
  • DOI: 10.1016/j.bmc.2015.01.030
  • Peer Reviewed / Open Access
• [Journal Article] New pyripyropene derivatives, highly SOAT2-selective inhibitors, improve hypercholesterolemia and atherosclerosis in atherogenic mouse model. (2015)
  • Author(s): Ohshiro, T.; Ohtawa, M.; Nagamitsu, T.; Matsuda, D.; Yagyu, H.; Davis, M. A.; Rudel, L. L.; Ishibashi, S.; Tomoda, H.
  • Journal Title: Journal of Pharmacology and Experimental Therapeutics Volume: 355 Issue: 2 Pages: 299-309
  • DOI: 10.1124/jpet.115.227348
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Synthesis and biological activity of 5-(4-methoxyphenyl)-oxazole derivatives (2015)
  • Author(s): D. Yamamuro, R. Uchida, M. Ohtawa, S. Arima, Y. Futamura, M. Katane, H. Homma, T. Nagamitsu, H. Osada, H. Tomoda
  • Journal Title: Bioorg. Medic. Chem. Lett. Volume: 25 Issue: 2 Pages: 313-316
  • DOI: 10.1016/j.bmcl.2014.11.042
  • Peer Reviewed / Open Access
• [Journal Article] In vitro metabolism of pyripyropene A and ACAT inhibitory activity of its metabolites. (2015)
  • Author(s): Ohshiro, T.; Matsuda, D.; Ohtawa, M.; Yamazaki, H.; Nagamitsu. T.; Tomoda, H.
  • Journal Title: J. Antibiot. 2015, 25, 313-316. Volume: 68 Issue: 1 Pages: 27-34
  • DOI: 10.1038/ja.2014.91
  • Peer Reviewed / Open Access
• [Journal Article] Design and synthesis of A-ring truncated analogs as potent ACAT2 selective inhibitors (2015)
  • Author(s): Ohtawa, M.; Omura, S.; Tomoda, H.; Nagamitsu, T
  • Journal Title: MEDCHEMNEWS Volume: 3 Pages: 25-31
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Regioselective mono-deprotection of di-tert-butylsilylene acetal derived from 1,3-diol with ammonium fluoride (2014)
  • Author(s): Ohtawa, M.; Tomoda, H.; Nagamitsu. T.
  • Journal Title: Bull. Chem. Soc. Jpn. Volume: 87 Issue: 1 Pages: 113-118
  • DOI: 10.1246/bcsj.20130237
  • NAID: 130004153261
  • 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 3 (2013)
  • Author(s): Ohtawa, M.; Yamazaki, H.; Ohte, S.; Matsuda, D.; Ohshiro, T.; Rudel, L. L.; Omura, S.; Tomoda, H.; Nagamitsu. T
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 23 Issue: 13 Pages: 3798-3801
  • DOI: 10.1016/j.bmcl.2013.04.075
  • 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 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] Structure-Activity Relationship Study and Total Synthesis of Pyripyropene A as a Potent ACAT2-Selective Inhibitor (2013)
  • Author(s): Ohtawa, M.; Omura, S.; Tomoda, H.; Nagamitsu, T.
  • Journal Title: Journal of Synthetic Organic Chemistry, Japan Volume: 71 Issue: 8 Pages: 830-843
  • DOI: 10.5059/yukigoseikyokaishi.71.830
  • NAID: 10031191019
  • ISSN: 0037-9980, 1883-6526
  • Peer Reviewed
• [Presentation] Structure-activity relationship study and total synthesis of pyripyropene A as a ACAT2-selective inhibitor (2015)
  • Author(s): Ohtawa, M.; Ohshiro, T.; Omura, S.; Tomoda. H.; Nagamitsu, T.
  • Organizer: Pacifichem 2015
  • Place of Presentation: Honolulu, USA
  • Year and Date: 2015-12-18
  • Int'l Joint Research
• [Presentation] Structure-activity relationship study and total synthesis of pyripyropene A as a ACAT2-selective inhibitor (2015)
  • Author(s): Ohtawa, M.; Ohshiro, T.; Omura, S.; Tomoda. H.; Nagamitsu, T.
  • Organizer: The 13th International Kyoto Conference on New Aspects of Organic Chemistry
  • Place of Presentation: 京都リーガロイヤルホテル
  • Year and Date: 2015-11-12
  • Int'l Joint Research
• [Presentation] ACAT2選択的阻害剤 pyripyropene A の構造簡略型誘導体の創製研究 (2014)
  • Author(s): 大多和正樹
  • Organizer: 第32回メディシナルケミストリーシンポジウム
  • Place of Presentation: 神戸国際会議場 (神戸)
  • Year and Date: 2014-11-26 – 2014-11-28
  • Invited
• [Presentation] ACAT2選択的阻害剤pyripyropene Aの構造簡略型誘導体の創製研究 (2013)
  • Author(s): 大多和正樹，寺山富明，大城太一，福田隆志，大村智，供田洋，長光亨
  • Organizer: 第31回メディシナルケミストリーシンポジウム
  • Place of Presentation: 広島/アステールプラザ
• [Presentation] ACAT2選択的阻害剤pyripyropene Aの構造簡略型誘導体の創製研究
  • Author(s): 大多和正樹，寺山富明，大城太一，福田隆志，大村智，供田洋，長光亨
  • Organizer: 第8回北里化学シンポジウム
  • Place of Presentation: 神奈川/北里大学理学部
• [Patent(Industrial Property Rights)] コレステロールアシル転移酵素アイソザイム2 (ACAT2) 阻害活性を有する新規医薬化合物 (2014)
  • Inventor(s): 供田洋、大多和正樹、大村智、長光亨
  • Industrial Property Rights Holder: 供田洋、大多和正樹、大村智、長光亨
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2014-129126
  • Filing Date: 2014-06-24