Design, synthesis and bioevaluation of new metalloenzymes inhibitors as therapeutic tools in degenerative diseases.

The extracellular matrix (ECM) is a complex structured network of secreted macromolecules and proteolytic enzymes that plays a vital role in the structure and development of tissues. Various types of proteinases are implicated in ECM remodelling and many of them are zinc-based metalloproteinases, belonging to the so called “Metzincins superfamily”. This superfamily of endopeptidases includes Matrix Metallo Proteinases (MMPs) and ADAMs or adamalysins (A Disintegrin and Metalloproteinases). In the recent years ADAM-17 (TACE), a member of the ADAMs, have emerged as attractive target for the treatment of inflammatory diseases like rheumatoid arthritis, and for some types of cancers, due to its involvement in the release of many types of cytokines, growth factors and many other cell-cell communication elements. During my PhD I focused my attention on the development and the synthesis of novel MMPs and ADAMs inhibitors which potency was assessed by fluorometric assay. In particular, the core of this PhD project has been the development of selective ADAM-17 inhibitors that could be useful therapeutic tools in the treatment of diseases where this enzyme is involved.