Design, Synthesis, Activity Evaluation And Structure-Activity Relationship Of Novel MMPs Inhibitors

Matrix Metalloproteinases (MMPs) are a family of zinc endopeptidases, which were found and studied recently possessing proteolytic potency of numerous proteins, such as gelatin, collagin and proteoglycin. As studied by cell biology and molecular biology, with the mechanism of normal physiological modulation, MMPs are capable of degrading almost all extracellular matrix (ECM) and participate a lot of physiological process, including tissue remodeling, pregnancy, wound healing. In recent pathological study, MMPs have been found highly expressed in ECM associated with many diseases, such as inflammation and cancer. Thus MMPs have been developed to be another important target for treatment of arthritis and tumor invasion and metastasis, and MMPs inhibitors become exactly necessary to be developed. Now a number of MMPs inhibitors are in clinical development for antiarthritis and anticancer therapy.Based on the known 3D-structure of MMPs-ligand complex, the binding mode and pharmacophore model of MMP-2 inhibitors were summarized. 3 series of target compounds were designed as inhibitors of MMPs with using obtained pharmacophore model and QSAR study of known inhibitors. The binding modes of one of series with MMP-2 were explored by the FlexX program and these binding modes can further guide the novel MMP-2 inhibitors design.Eighty-five target compounds were synthesized and identified by ¹HNMR and MS, during which two hundred and fifty-three compounds were obtained and one hundred and thirty compounds were unreported. Thirty-one compounds were also identified by HRFAB. The synthesized target compounds were tested for their inhibitory activity towards the MMPs (MMP-1, MMP-2, MMP-9), IC₅₀ of twenty-seven compounds were given. These compounds exhibited potent inhibitory activity, some showed high selectivity for MMP-2 over MMP-1 and MMP-9.The inhibitory activity data and structure-activity relationships of synthesized compounds offered detailed information for design and synthesis of new compounds.