Phosphonamide-Based Metalloproteinase Inhibitors: A New Approach to the Development of Safer Metalloproteinase Inhibitors

Two closely related zinc metalloprotease (MP) families i.e. MMPs (matrix metalloproteinases) and ADAMs (a disintegrin-like and metalloproteinase-containing protein) including ADAMTSs (ADAMs with one or more thrombospondin domain) have lately become important therapeutic targets in drug discovery research. Although a vast number of MMP inhibitors have been developed in recent years, the results from clinical trials with these compounds have been insufficient for their approval as effective and safe drugs. One of the obstacles to the success MMP inhibitors in clinical development has been the adverse effects caused by undesirable inhibition of non-target MMPs and / or ADAMs. A series of phosphonamide-based compounds recently disclosed by our laboratory includes potent metalloproteinase inhibitors with increased enzyme selectivity relative to the corresponding sulfonamide-based compounds. This increased selectivity arises from the chirality of the phosphonamides core structure, which alters the inhibitor binding mode at the active site of the enzyme. In addition, these phosphonamidebased compounds may be useful for the development of safe metalloproteinase inhibitors, as antedrugs, since phosphonamide structures are known for their instability in the body. This instability may provide a solution to the problem of side effects known to conventional MMP inhibitors and allow new applications for metalloproteinase inhibitors in general.