The design of selective non-substrate-based matrix metalloproteinase inhibitors

A significant number of the matrix metalloproteinase (MMP) gene family of zinc-dependent enzymes have been implicated in a variety of diseases. This has fuelled considerable interest from the pharmaceutical industry in the identification and development of inhibitors of this class of enzyme. A number of such compounds have entered development over the last 10 years and several have progressed to late-stage clinical studies, particularly in the field of oncology. These so-called first generation inhibitors were derived from substrate recognition peptide sequences and have a very broad inhibitory profile within the MMP family. As the field of metalloproteinase research has expanded and our knowledge has increased, new gene sub-families such as the ADAM and ADAMTS metalloproteinases have been identified, and the first generation inhibitors have also been shown to inhibit a number of these new enzymes. Thus, it is hypothesized that the broad inhibitory profile of these first generation compounds could explain some of the side effects observed in man. Therefore, more recent work in this field has centered on the identification of inhibitors with different selectivity profiles and the effect of such inhibitors in models of a variety of different diseases. Another drawback of the early development candidates was their modest pharmacokinetic profile which, in part, was due to their peptidomimetic nature. Hence, another area of focus for researchers in this field has been to improve DMPK parameters and to move away from peptidomimetics to truly non-substrate-based inhibitors. This review focuses on recent advances in these two key areas of MMP research.