Discovery of a new chemical lead for a matrix metalloproteinase inhibitor

A series of N-benzoyl γ-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 γ-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 γ-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.

A series of N-benzoyl γ-aminobutyric hydroxamic acids were synthesized and evaluated as matrix metalloproteinase inhibitors. Optimization of the N-benzoyl residue and γ-amino butyric hydroxamic acid moiety resulted in the discovery of two novel MMP inhibitors (compounds 10 and 11).Figure optionsDownload as PowerPoint slide