Development of synthetic ADAMTS7 selective inhibitors potentially useful for the treatment of cardiovascular diseases

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

Identification of N-Acyl Hydrazones as New Non-Zinc-Binding MMP-13 Inhibitors by Structure-Based Virtual Screening Studies and Chemical Optimization

Matrix metalloproteinase 13 plays a central role in osteoarthritis (OA), as its overexpression induces an excessive breakdown of collagen that results in an imbalance between collagen synthesis and degradation in the joint, leading to progressive articular cartilage degradation. Therefore, MMP-13 has been proposed as a key therapeutic target for OA. Here we have developed a virtual screening workflow aimed at identifying selective non-zinc-binding MMP-13 inhibitors by targeting the deep S1 & PRIME; pocket of MMP-13. Three ligands were found to inhibit MMP-13 in the & mu;M range, and one of these showed selectivity over other MMPs. A structure-based analysis guided the chemical optimization of the hit compound, leading to the obtaining of a new N-acyl hydrazone-based derivative with improved inhibitory activity and selectivity for the target enzyme