Masaru Sakai

Publications (6)16.79 Total impact

• Article: Synthesis, further biological evaluation and pharmacodynamics of newly discovered inhibitors of TNF-alpha production.

  Toshiaki Matsui, Takashi Kondo, Shingo Nakatani, Nagashige Omawari, Masaru Sakai, Hideaki Mori, Akihito Ogata, Junya Kato, Hiroyuki Ohno, Takaaki Obata, Hisao Nakai, Masaaki Toda
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  ABSTRACT: (1S,2R)-2-Acylamino-1-methyl-2-phenylethyl phosphate derivatives 2a, 2b, 3a, and 5a, which are conformationally restricted and metabolically stable analogues of (2R)-2-acylamino-2-phenylethyl phosphate derivatives 1a and 1b, are a new class of inhibitors of TNF-alpha production. More efficient alternative synthesis of a key intermediate, (1R,2S)-1-amino-1-(3-methoxyphenyl)propan-2-ol hydrochloride (9), was achieved using one-step, three-component coupling of 3-methoxyphenyl boronic acid (13), (5S)-2,2,5-trimethyl-1,3-dioxolan-4-ol (14), and amino diphenyl methane (15), [as reported in J. Am. Chem. Soc. 1998, 120, 11798]. Evaluation of the hypotensive activity of these compounds was done to assess one of their side effects. Among the compounds tested, the above-mentioned four compounds (2a, 2b, 3a, and 5a) were identified as inhibitors with both sufficient potency and an acceptable safety margin regarding their hypotensive activity. The pharmacodynamics of these compounds were also investigated. Single-dose pharmacokinetic data for compounds 2a, 2b, 3a, and 5a are displayed. These compounds were estimated to be mainly metabolized by the liver in the species tested based on their in vitro stability in tissue homogenates and plasma. A representative compound, 2a, showed good linearity of its plasma concentration after intravenous injection.
  Bioorganic & Medicinal Chemistry 10/2003; 11(18):3937-43. · 2.92 Impact Factor
• Article: Highly potent inhibitors of TNF-alpha production. Part I: discovery of new chemical leads and their structure-activity relationships.

  Toshiaki Matsui, Takashi Kondo, Yoshitaka Nishita, Satoshi Itadani, Shingo Nakatani, Nagashige Omawari, Masaru Sakai, Shuichi Nakazawa, Akihito Ogata, Hideaki Mori, Kouichiro Terai, Wataru Kamoshima, Hiroyuki Ohno, Takaaki Obata, Hisao Nakai, Masaaki Toda
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  ABSTRACT: Discovery of new chemical leads of inhibitors for TNF-alpha production starting from the chemical modification of 1 is reported. Further biological studies of 1 to disclose the site of its action strongly suggested that 1 inhibits LPS-induced TNF-alpha expression in the liver and spleen of mice. Structure-activity relationships (SARs) are also discussed and full details including the chemistry are reported.
  Bioorganic & Medicinal Chemistry 01/2003; 10(12):3757-86. · 2.92 Impact Factor
• Article: Discovery of novel phosphonic acid derivatives as new chemical leads for inhibitors of TNF-alpha production.

  Toshiaki Matsui, Shinya Takahashi, Naoki Matsunaga, Kazunori Nakamura, Nagashige Omawari, Masaru Sakai, Wataru Kamoshima, Kouichiro Terai, Hiroyuki Ohno, Takaaki Obata, Hisao Nakai, Masaaki Toda
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  ABSTRACT: 2-(Acylamino)benzylphosphonic acid 6 derived from an artificial substrate of sphingomyelinase was found to show inhibitory activity of TNF-alpha production. Structural optimization was started with the chemical modification of 6. The discovery of another chemical leads 7, 8, 10 and 16 for the development of structurally new inhibitors of TNF-alpha production is reported.
  Bioorganic & Medicinal Chemistry 01/2003; 10(12):3807-15. · 2.92 Impact Factor
• Article: Highly potent inhibitors of TNF-alpha production. Part II: metabolic stabilization of a newly found chemical lead and conformational analysis of an active diastereoisomer.

  Toshiaki Matsui, Takashi Kondo, Yoshitaka Nishita, Satoshi Itadani, Hiroshi Tsuruta, Setsuko Fujita, Nagashige Omawari, Masaru Sakai, Shuichi Nakazawa, Akihito Ogata, Hideaki Mori, Wataru Kamoshima, Kouichiro Terai, Hiroyuki Ohno, Takaaki Obata, Hisao Nakai, Masaaki Toda
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  ABSTRACT: Design and synthesis of metabolically stabilized inhibitors of TNF-alpha production, which could be new drug candidates, are reported. Conformational analysis of an active diastereoisomer was performed based on biological evaluations of the conformationally fixed indane derivatives 17 and 18. Structure-activity relationships (SARs) based on biological evaluations of the optically active derivatives are also discussed. Full details including chemistry are reported.
  Bioorganic & Medicinal Chemistry 01/2003; 10(12):3787-805. · 2.92 Impact Factor
• Article: Highly potent inhibitors of TNF-alpha production. Part 1: Discovery of chemical leads.

  Toshiaki Matsui, Takashi Kondo, Yoshitaka Nishita, Satoshi Itadani, Shingo Nakatani, Nagashige Omawari, Masaru Sakai, Shuichi Nakazawa, Akihito Ogata, Hiroyuki Ohno, Takaaki Obata, Hisao Nakai, Masaaki Toda
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  ABSTRACT: The discovery of 2-acylamino-2-phenylethyl disodium phosphates and as structurally novel inhibitors of TNF-alpha production is reported. Structure-activity relationships (SARs) are also discussed.
  Bioorganic & Medicinal Chemistry Letters 04/2002; 12(6):903-5. · 2.55 Impact Factor
• Article: Highly potent inhibitors of TNF-alpha production. Part 2: identification of drug candidates.

  Toshiaki Matsui, Takashi Kondo, Yoshitaka Nishita, Satoshi Itadani, Hiroshi Tsuruta, Setsuko Fujita, Nagashige Omawari, Masaru Sakai, Shuichi Nakazawa, Akihito Ogata, Hideaki Mori, Hiroyuki Ohno, Takaaki Obata, Hisao Nakai, Masaaki Toda
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  ABSTRACT: Metabolic stabilization of the chemical lead 1, which is a structurally novel inhibitor of TNF-alpha production, was accomplished by introducing a (1S)-methyl group into the optically active backbone. As a result, 2, 3 and 4 were identified as drug candidates and evaluated pharmacologically. The analysis of an active conformer was also carried out.
  Bioorganic & Medicinal Chemistry Letters 04/2002; 12(6):907-10. · 2.55 Impact Factor