Lead optimisation of selective non-zinc binding inhibitors of MMP13. Part 2

Bioorg Med Chem Lett. 2012 Jan 1;22(1):271-7. doi: 10.1016/j.bmcl.2011.11.034. Epub 2011 Nov 16.

Abstract

Directed screening has identified a novel series of non-zinc binding MMP13 inhibitors that possess good levels of activity whilst demonstrating excellent selectivity over related MMPs. A lead optimisation campaign has delivered compounds with enhanced MMP13 potency, good selectivity and acceptable bioavailability profiles leading to a predicted twice-a-day dosing regimen in man.

MeSH terms

  • Animals
  • Chemistry, Pharmaceutical / methods*
  • Dogs
  • Drug Design
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Inhibitory Concentration 50
  • Matrix Metalloproteinase 13 / chemistry*
  • Matrix Metalloproteinase Inhibitors*
  • Models, Chemical
  • Models, Molecular
  • Osteoarthritis / drug therapy
  • Rats
  • Solubility
  • Structure-Activity Relationship
  • Zinc / chemistry*

Substances

  • Enzyme Inhibitors
  • Matrix Metalloproteinase Inhibitors
  • Matrix Metalloproteinase 13
  • Zinc