Thieno[2,3-d]pyrimidine-2-carboxamides bearing a carboxybenzene group at 5-position: highly potent, selective, and orally available MMP-13 inhibitors interacting with the S1″ binding site

Bioorg Med Chem. 2014 Oct 1;22(19):5487-505. doi: 10.1016/j.bmc.2014.07.025. Epub 2014 Aug 7.

Abstract

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.

MeSH terms

  • Administration, Oral
  • Benzene Derivatives / administration & dosage
  • Benzene Derivatives / chemistry*
  • Benzene Derivatives / pharmacology
  • Binding Sites / drug effects
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Humans
  • Matrix Metalloproteinase 13 / metabolism*
  • Matrix Metalloproteinase Inhibitors / administration & dosage*
  • Matrix Metalloproteinase Inhibitors / chemistry
  • Matrix Metalloproteinase Inhibitors / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Pyrimidines / administration & dosage
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Benzene Derivatives
  • Matrix Metalloproteinase Inhibitors
  • Pyrimidines
  • thieno(2,3-d)pyrimidine-2-carboxamide
  • Matrix Metalloproteinase 13