Orally active achiral N-hydroxyformamide inhibitors of ADAM-TS4 (aggrecanase-1) and ADAM-TS5 (aggrecanase-2) for the treatment of osteoarthritis

Bioorg Med Chem Lett. 2011 Jun 1;21(11):3301-6. doi: 10.1016/j.bmcl.2011.04.028. Epub 2011 Apr 13.

Abstract

A new achiral class of N-hydroxyformamide inhibitor of both ADAM-TS4 and ADAM-TS5, 2 has been discovered through modification of the complex P1 group present in historical inhibitors 1. This structural change improved the DMPK properties and greatly simplified the synthesis whilst maintaining excellent cross-MMP selectivity profiles. Investigation of structure-activity and structure-property relationships in the P1 group resulted in both ADAM-TS4 selective and mixed ADAM-TS4/5 inhibitors. This led to the identification of a pre-clinical candidate with excellent bioavailability across three species and predicting once daily dosing kinetics.

MeSH terms

  • ADAM Proteins / antagonists & inhibitors*
  • ADAMTS4 Protein
  • ADAMTS5 Protein
  • Administration, Oral
  • Animals
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Formamides / chemical synthesis*
  • Formamides / chemistry
  • Humans
  • Molecular Structure
  • Osteoarthritis / drug therapy
  • Procollagen N-Endopeptidase / antagonists & inhibitors*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Swine

Substances

  • Enzyme Inhibitors
  • Formamides
  • ADAM Proteins
  • ADAMTS5 Protein
  • ADAMTS5 protein, human
  • Procollagen N-Endopeptidase
  • ADAMTS4 Protein