On the basis of X-ray co-crystal structures of matrix metalloproteinase-13 (MMP-13) in complex with its inhibitors, our structure-based drug design (SBDD) strategy was directed to achieving high affinity through optimal protein-ligand interaction with the unique S1″ hydrophobic specificity pocket. This report details the optimization of lead compound 44 to highly potent and selective MMP-13 inhibitors based on fused pyrimidine scaffolds represented by the thienopyrimidin-4-one 26c. Furthermore, we have examined the release of collagen fragments from bovine nasal cartilage in response to a combination of IL-1 and oncostatin M.
Keywords: MMP-13; Matrix metalloproteinase; OA; Osteoarthritis; Structure-based drug design; Thieno[2,3-d]pyrimidin-4-one; X-ray crystallography.
Copyright © 2014. Published by Elsevier Ltd.