Discovery of a new chemical lead for a matrix metalloproteinase inhibitor.
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.
Minase Research Institute, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan. ikura@ono.co.jp
Masahiro
M
Ikura
Shingo
S
Nakatani
Shingo
S
Yamamoto
Hiromu
H
Habashita
Tsuneyuki
T
Sugiura
Kanji
K
Takahashi
Koji
K
Ogawa
Hiroyuki
H
Ohno
Hisao
H
Nakai
Masaaki
M
Toda
D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors