ADAMTS (A Disintegrin And Metalloproteinase with Thrombospondin Motifs) family belongs to the superfamily of Metzincins and comprises 19 secreted zinc metalloproteinases. An altered homeostasis of ADAMTS enzymes is associated to pathological conditions, rendering these proteases an attractive pharmacological target. In particular, in vivo studies confirmed that ADAMTS7 is involved in both Coronary Artery Disease (CAD) and atherosclerosis. Overall, recent findings revealed the role of ADAMTS7 as promising target for intervention and its inhibition as a potential pharmacological approach. So far, no selective ADAMTS7 inhibitors have been reported.
My Thesis project focused on the synthesis of potent and selective hydroxamate-based ADAMTS7 inhibitors, starting from the already published ADAMTS7 inhibitor EDV33. The optimization process led to the synthesis of new compounds, which were tested for enzymatic activity and selectivity by a fluorometric assay by Dr. Santamaria (Imperial College London, UK).
The optimized compounds displayed a good activity on the target enzyme and a significant improvement in selectivity.
Even though further modifications have to be done in order to develop a SAR study and achieve a high affinity and selectivity for ADAMTS7, final compounds reported in this Thesis showed promising results, thus representing a good starting point for future optimizations
