Schematic overview of the varied strategies for the discovery of monoamine oxidase inhibitors.

Matrix metalloproteinases (MMPs) belong to a family of closely related calcium- and zinc-dependent endopeptidases involved in the degradation and remodeling of extracellular matrix (ECM) proteins that are associated with the tumorigenic processes. MMPs promote tumor invasion and metastasis, regulating host defense mechanisms and normal cell function. Thus, MMP inhibitors (MMPIs) are expected to be useful chemotherapeutic agents for the treatment of malignant cancer, osteoarthritis, and rheumatoid arthritis. A vast number of small molecular MMPIs have been developed in recent years. Although there have been considerable preclinical and clinical studies on these inhibitors, most of the effective candidates in clinical trials, however, have yielded unsatisfactory results, thus they are as yet unavailable for use as therapeutic drugs. Currently, more efforts have been directed to the design of specific inhibitors towards certain MMP family members for selective usage. This review will focus primarily on an analysis of recent developed MMPIs that have entered preclinical or clinical trials, and recently registered patents with regard to new highly selective MMPIs in USA or patent applications related to the specific inhibitors of MMPs. We also analyze the clinical failure and discuss the possible strategies to best optimize the development of these novel agents.

Pyrrolidine scaffold has been widely used to design a variety of N-heterocyclic derivatives towards various targets. Amongst them, matrix metalloproteins (MMPs) and aminopeptidase N (APN) represent two kinds of important metalloproteinase targets which have been proved to be tightly related to tumor proliferation, invasion, metastasis and angiogenesis. As a result, their respective inhibitors, namely MMP inhibitors (MMPIs) and APN inhibitors (APNIs), have been systematically studied in our group for many years. Recent advances in the elucidation of MMPIs and APNIs based on the pyrrolidine platforms are briefly reviewed in this paper.