Synthetic study of membrane permeable inhibitor of HTLV-I protease

• Project/Area Number: 18590110
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Kyoto Pharmaceutical University
• Principal Investigator: KIMURA Tooru Kyoto Pharmaceutical University, 薬学部, 准教授 (70204980)
• Project Period (FY): 2006 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥3,310,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥510,000); Fiscal Year 2008: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2007: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2006: ¥1,100,000 (Direct Cost: ¥1,100,000)
• Keywords: 医薬品化学 / プロテアーゼ阻害剤 / HTLV-I / レトロウイルス / プロテアーゼ / 阻害剤 / 遷移状態ミメティック

Research Abstract

アスパルティックプロテアーゼ阻害剤の設計は, 基質遷移状態概念誘導体を基質の切断部位に組み込み, これを基に構造変換を行うといった手法が一般的である. 我々が既に合成したHTLV-Iプロテアーゼの基質部位p19/p24に相当するオクタペプチド(PQVL*PVMH)にHMCを導入し多少の構造変換を行った化合物KMI-10162は, HTLV-Iプロテアーゼ阻害活性を有していた. そこでこの化合物をリードに, 膜透過性を上昇させるようデザインした阻害剤を合成した.

Research Products

• [Journal Article] Locking the two ends of tetrapeptidic HTLV-I protease inhibitors inside the enzyme (2008)
  • Author(s): Meihui Zhang, Jeffrey-Tri Nguyen, Henri-Obadja Kumada, Tooru Kimura, Maosheng Cheng,Yoshio Hayashi, Yoshiaki Kiso
  • Journal Title: Bioorg. Med. Chem. 16(14) Pages: 6880-6890
  • Peer Reviewed
• [Journal Article] Synthesis and activity of tetrapeptidic HTLV-1 protease inhibitors possessing different P3-cap moieties (2008)
  • Author(s): Meihui Zhang, Jeffrey-Tri Nguyen, Henri-Obadja Kumada, Tooru Kimura, Maosheng Cheng, Yoshio Hayashi, Yoshiaki Kiso
  • Journal Title: Bioorg. Med. Chem 16(10) Pages: 5795-5802
  • Peer Reviewed
• [Journal Article] Truncation and non-natural amino acid substitution studies on HTLV-I protease hexapeptidic inhibitors (2008)
  • Author(s): Jeffrey-Tri Nguyen, Meihui Zhang, Henri-Obadja Kumada, Ayako Itami, Keiji Nishiyama, Tooru Kimura, Maosheng Cheng, Yoshio Hayashi, Yoshiaki Kiso
  • Journal Title: Bioorg. Med. Chem. Lett 18(1) Pages: 366-370
  • Peer Reviewed
• [Journal Article] Synthesis and activity of tetrapeptidic HTLV-1 protease inhibitors possessing different P3-cap moieties. (2008)
  • Author(s): Meihui Zhang, Jeffrey-Tri Nguyen, HenriObadja Kumada, et al.
  • Journal Title: Bioorg. Med. Chem. 16(10) Pages: 5795-5802
  • Peer Reviewed
• [Journal Article] Locking the two ends of tetrapeptidic HTLV-I protease inhibitors inside the enzyme. (2008)
  • Author(s): Meihui Zhang, Jeffrey-Tri Nguyen, HenriObadja Kumada, et al.
  • Journal Title: Bioorg. Med. Chem. 16(14) Pages: 6880-6890
  • Peer Reviewed
• [Journal Article] Truncation and non-natural amino acid substitution studies on HTLV-I protease hexaetidic inhibitors. (2008)
  • Author(s): J.-T.Nguyen, M.Zhang, H.-O.Kumada, A.Itami, K.Nishiyama, et. al.
  • Journal Title: Bioorg.Med.Chem.Lett. 18(1) Pages: 366-370
  • Peer Reviewed
• [Journal Article] Synthesis and antiviral property of allophenylnorstatine-based HIV protease inhibitors incorporating D-cysteine derivatives as P2/P3 moieties (2007)
  • Author(s): Ei'ichi Ami, Koichiro Nakahara, Akihiko Sato, Jeffrey-Tri Nguyen, Koushi Hidaka, Yoshio Hamada, Shingo Nakatani, Tooru Kimura, Yoshio Hayashi, Yoshiaki Kiso
  • Journal Title: Bioorg. Med. Chem. Lett 17(15) Pages: 4213-4217
  • Peer Reviewed
• [Journal Article] Chipping at large, potent human T-cell leukemia virus type 1 protease inhibitors to uncover smaller, equipotent inhibitors (2007)
  • Author(s): Tooru Kimura, Jeffrey-Tri Nguyen, Hikoichiro Maegawa, Keiji Nishiyama, Yasuhiro Arii, Yasuko Matsui, Yoshio Hayashi and Yoshiaki Kiso
  • Journal Title: Bioorg. Med. Chem. Lett 17(12) Pages: 3276-3280
  • Peer Reviewed
• [Journal Article] Design and synthesis of BACE1 inhibitors containing a novel norstatine derivative (2R, 3R)-3-amino-2-hydroxy-4-(phenylthio)butyric acid (2007)
  • Author(s): Zyta Ziora, Soko Kasai, Koushi Hidaka, Ayaka Nagamine, Tooru Kimura, Yoshio Hayashi, Yoshiaki Kiso
  • Journal Title: Bioorg. Med. Chem. Lett 17(6) Pages: 1629-1633
  • Peer Reviewed
• [Journal Article] Synthesis and antiviral property of allophenylnorstatine-based HIV protease inhibitors incorporaingD-cyteine derivatives as P2/P3 moieties (2007)
  • Author(s): E.Ami, K.Nakahara, A.Sato, J.-T.Nguyen, K.Hidaka, et. al.
  • Journal Title: Bioorg.Med.Chem.Lett. 17(15) Pages: 4213-4217
  • Peer Reviewed
• [Journal Article] Chipping at large,potent human T-cell leukemia virus type 1 protease inhibitors to uncover smaller,equipotent inhibitors (2007)
  • Author(s): T.Kimura, J.-T.Nguyen, H.Maegawa, K.Nishiyama, Y.Arii, et. al.
  • Journal Title: Bioorg.Med.Chem.Lett. 17(12) Pages: 3276-3280
  • Peer Reviewed
• [Journal Article] Design and synthesis of BASE1 inhibitors containing a novel norstatine derivative(2R,3R) -3-amino-2-hydroxy-4-(phenylthio)butyric acid. (2007)
  • Author(s): Z.Ziora, S.Kasai, K.Hidaka, A.Nagamine, T.Kimura, Y.Hayashi, et al.
  • Journal Title: Bioorg. Med. Chem. Lett 17(6) Pages: 1629-1633
• [Journal Article] Development of first photoresponsive prodrug of paclitaxel (2006)
  • Author(s): Mariusz Skwarczynski, Mayo Noguchi, Shun Hirota, Youhei Sohma, Tooru Kimura, Yoshio Hayashi, Yoshiaki Kiso
  • Journal Title: Bioorg. Med. Chem. Lett 16(17) Pages: 4492-4496
  • Peer Reviewed
• [Journal Article] β-Secretase inhibitors : Modification at the P4 position and improvement of inhibitory activity in cultured cell (2006)
  • Author(s): Yoshio Hamada, Naoto Igawa, Hayato Ikari, Zyta Ziora, Jeffrey-Tri Nguyen, Abdellah Yamani, Koushi Hidaka, Tooru Kimura, Kazuki Saito, Yoshio Hayashi, Maiko Ebina, Shoichi Ishiura, Yoshiaki Kiso
  • Journal Title: Bioorg. Med. Chem. Lett 16(16) Pages: 4354-4359
  • Peer Reviewed
• [Journal Article] "O-Acyl isopeptide method" for the efficient synthesis of difficult sequence-containing peptides : use of "O-acyl isodipeptide unit" (2006)
  • Author(s): Youhei Sohma, Atsuhiko Taniguchi, Mariusz Skwarczynski, Taku Yoshiya, Fukue Fukao, Tooru Kimura, Yoshio Hayashi, Yoshiaki Kiso
  • Journal Title: Tetrahedron Letters 47(18) Pages: 3013-3017
  • Peer Reviewed
• [Journal Article] O-N Intramolecular acyloxy migration of typical protective groups in hydroxyamino acids (2006)
  • Author(s): Mariusz Skwarczynski, Youhei Sohma, Mayo Noguchi, Tooru Kimura, Yoshio Hayashi, Yoshiaki Kiso
  • Journal Title: J. Org. Chem 71(6) Pages: 2542-2545
  • Peer Reviewed
• [Journal Article] Design and synthesis of potent β-secretase (BACE1) inhibitors with P1' carboxylic acid bioisosteres (2006)
  • Author(s): Tooru Kimura, Yoshio Hamada, Monika Stochaj, Hayato Ikari, Ayaka Nagamine, Hamdy Abdel-Rahman, Naoto Igawa, Koushi Hidaka, Jeffrey-Tri Nguyen, Kazuki saito, Yoshio Hayashi, Yoshiaki Kiso
  • Journal Title: Bioorg. Med. Chem. Lett 16(9) Pages: 2380-2386
  • Peer Reviewed
• [Journal Article] Design and synthesis of potent β-secretase (BACE1) inhibitors with P1'carboxylic acid bioisosteres. (2006)
  • Author(s): T.Kimura, Y.Hamada, M.Stochaj, H.Ikari, A.Nagamine, et al.
  • Journal Title: Bioorg. Med. Chem. Lett 16(9) Pages: 2380-2386
• [Journal Article] O-N Intramolecular acyloxy migration of typical protective groups in hydroxyamino acids. (2006)
  • Author(s): M.Skwarczynski, Y.Sohma, M.Noguchi, T.Kimura, Y.Hayashi, et al.
  • Journal Title: J.Org.Chem 71(6) Pages: 2542-2545
• [Journal Article] "O-Acyl isopeptide method"for the efficient synthesis of difficult sequence-containing peptides : use of "O-acyl isodipeptide unit." (2006)
  • Author(s): Y.Sohma, A.Taniguchi, M.Skwarczynski, T.Yoshida, et al.
  • Journal Title: Tetrahedron Letters 47(18) Pages: 3013-3017
• [Journal Article] β-Secretase inhibitors : Modification at the P4 position and improvement of inhibitory activity in cultured cell. (2006)
  • Author(s): Y.Hamada, N.Igawa, H.Ikari, Z.Ziora, J-T.Nguyen, A.Yamani.et al.
  • Journal Title: Bioorg. Med. Chem. Lett 16(16) Pages: 4354-4359
• [Journal Article] Development of first photo responsive prod rug of paclitaxel. (2006)
  • Author(s): M.Skwarczynski, M.Noguchi, S.Hirota, Y.Sohma, T.Kimura, Y.Hayashi, et al.
  • Journal Title: Bioorg. Med. Chem. Lett 16(17) Pages: 4492-4496
• [Presentation] Road to HTLV-I protease inhibition. (2008)
  • Author(s): Jeffrey-Tri Nguyen, Meihui Zhang, Ayako Itami, et al.
  • Organizer: International Symposium on Integrated Medicinal Science
  • Place of Presentation: 京都
  • Year and Date: 2008-12-13
• [Presentation] Road to HTLV-I protease inhibition (2008)
  • Author(s): Jeffrey-Tri Nguyen, Meihui Zhang, Ayako Itami, Hikoichiro Maegawa, Keiji Nishiyama, Tooru Kimura, Yoshio Hayashi, Maosheng Cheng, Yoshiaki Kiso
  • Organizer: International Symposium on Integrated Medicinal Science
  • Place of Presentation: Kyoto, Japan
• [Presentation] Rational Drug Design of HTLV-I Protease Inhibitors from Octapeptides to Tetrapeptides (2007)
  • Author(s): J.-T, Nguyen, M. Zhang, A. Itami, H. Maegawa, K. Nishiyama, T. Kimura, Y. Hayashi, M. Cheng and Y. Kiso
  • Organizer: 20th American Peptide Symposium : Peptides for Youth
  • Place of Presentation: Montreal, Canada
• [Presentation] Rational Drug Design of HTLU- Protease Inhibitors from Octapeptides to Tetrapetides (2007)
  • Author(s): J.-T.Nguyen, M.Zhang, A.Itami, H.Maegawa, K.Nishiyama, et. al.
  • Organizer: 20th American Peptide Symposium
  • Place of Presentation: Montreal,Canada
• [Remarks]
  • URL: http://www.kyoto-phu.ac.jp/labo/yakuhin/
• [Remarks]
  • URL: http://www.kyoto-phu.ac.jp/labo/yakuhin/