The design and synthesis of novel N-hydroxyformamide inhibitors of ADAM-TS4 for the treatment of osteoarthritis

Bioorg Med Chem Lett. 2011 Mar 1;21(5):1376-81. doi: 10.1016/j.bmcl.2011.01.036. Epub 2011 Jan 18.

Abstract

Two series of N-hydroxyformamide inhibitors of ADAM-TS4 were identified from screening compounds previously synthesised as inhibitors of matrix metalloproteinase-13 (collagenase-3). Understanding of the binding mode of this class of compound using ADAM-TS1 as a structural surrogate has led to the discovery of potent and very selective inhibitors with favourable DMPK properties. Synthesis, structure-activity relationships, and strategies to improve selectivity and lower in vivo metabolic clearance are described.

MeSH terms

  • ADAM Proteins / antagonists & inhibitors*
  • ADAMTS4 Protein
  • Anti-Inflammatory Agents / chemical synthesis*
  • Anti-Inflammatory Agents / chemistry
  • Anti-Inflammatory Agents / pharmacology
  • Drug Design*
  • Enzyme Activation / drug effects
  • Formamides / chemical synthesis*
  • Formamides / chemistry
  • Formamides / pharmacology
  • Humans
  • Inhibitory Concentration 50
  • Models, Molecular
  • Osteoarthritis / drug therapy
  • Procollagen N-Endopeptidase / antagonists & inhibitors*
  • Quantitative Structure-Activity Relationship

Substances

  • Anti-Inflammatory Agents
  • Formamides
  • ADAM Proteins
  • Procollagen N-Endopeptidase
  • ADAMTS4 Protein