A Potent Nonpeptidic Matrix Metalloproteinase Inhibitor

Inhibitors of matrix metalloproteinases (MMPs) are comprised of a zinc-binding functional group which targets the inhibitor to the catalytic zinc within the active site of the enzyme, and a peptidomimetic portion which increases the affinity of the inhibitor to the enzyme active site, thereby mimicking the natural peptide substrate. The majority of first generation inhibitors of MMPs were first described in the literature in the late 1980s. These matrix metalloproteinase inhibitors (MMPIs) were designed as inhibitors of fibroblast interstitial collagenase (MMP-1) and consisted of a hydroxamic acid as the zinc-binding functional group and a LeuLeuPhe or LeuPhe as a mimetic of the preferred substrate of MMP-1 (Fig. 1) (1). These early compounds were often broad-spectrum MMPIs, with potent inhibitory activity against fibroblast collagenase, stromelysin-1 (MMP-3), and the gelatinases (MMP-2 and MMP-9). As peptides, they suffered from low bioavailability and rapid metabolism, and as hydroxamic acids they were potentially mutagenic.