The Design, Structure, and Therapeutic Application of Matrix Metalloproteinase Inhibitors

Jerry   W.   Skiles; Nina   C.   Gonnella; Arco   Y.   Jeng

Abstract

Matrix metalloproteinases (MMPs) are a family of zinc-containing enzymes involved in the degradation and remodeling of extracellular matrix proteins. The activities of these enzymes are well regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs). Chronic stimulation of MMP activities due to an imbalance in the levels of MMPs and TIMPs has been implicated in the pathogenesis of a variety of diseases such as cancer, osteoarthritis, and rheumatoid arthritis. Thus, MMP inhibitors are expected to be useful for the treatment of these disorders. This article reviews briefly the biochemistry of MMPs and evidence for their pathogenic roles using molecular biology approaches. Biomolecular structures used in the design of MMP inhibitors are thoroughly covered. Major emphasis is on recently published potent, small molecular weight MMP inhibitors and their pharmacological properties. Finally, available clinical results of compounds in development are summarized.

Keywords: Metalloproteinase inhibitors, angiogenesis, tumor induced, hydroxamate moiety, non peptidic sulfonamide, uninhibited catalytic domain, gelatinase, murine model, spiro cyclopentyl, Biaryl oxime