Discovery of a new chemical lead for a matrix metalloproteinase inhibitor |
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Authors: | Ikura Masahiro Nakatani Shingo Yamamoto Shingo Habashita Hiromu Sugiura Tsuneyuki Takahashi Kanji Ogawa Koji Ohno Hiroyuki Nakai Hisao Toda Masaaki |
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Institution: | Minase Research Institute, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan. ikura@ono.co.jp |
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Abstract: | A series of N-benzoyl gamma-aminobutyric hydroxamic acids were synthesized and evaluated as matrix metalloproteinase inhibitors. First, we focused on chemical modification of the N-benzoyl residue. Introduction of electron-rich para-substituents was effective to increase the inhibitory activity. Especially, some of the analogs with relatively more planar N-acyl residues, such as 10 and 11, demonstrated more potent activity. Second, chemical modification of the gamma-aminobutyric hydroxamic acid moiety was carried out to optimize the three-dimensional arrangement of the two pharmacophores (hydroxamic acid and N-acyl residues). Among the tested, the gamma-aminobutyric hydroxamic acid moiety was found to be the best spacer for connecting the above-mentioned two pharmacophores. Synthesis and structure-activity relationships are discussed. |
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