Discovery of novel, highly potent, and selective quinazoline-2-carboxamide-based matrix metalloproteinase (MMP)-13 inhibitors without a zinc binding group using a structure-based design approach

J Med Chem. 2014 Nov 13;57(21):8886-902. doi: 10.1021/jm500981k. Epub 2014 Oct 15.

Abstract

Matrix metalloproteinase-13 (MMP-13) has been implicated to play a key role in the pathology of osteoarthritis. On the basis of X-ray crystallography, we designed a series of potent MMP-13 selective inhibitors optimized to occupy the distinct deep S1' pocket including an adjacent branch. Among them, carboxylic acid inhibitor 21k exhibited excellent potency and selectivity for MMP-13 over other MMPs. An effort to convert compound 21k to the mono sodium salt 38 was promising in all animal species studied. Moreover, no overt toxicity was observed in a preliminary repeat dose oral toxicity study of compound 21k in rats. A single oral dose of compound 38 significantly reduced degradation products (CTX-II) released from articular cartilage into the joint cavity in a rat MIA model in vivo. In this article, we report the discovery of highly potent, selective, and orally bioavailable MMP-13 inhibitors as well as their detailed structure-activity data.

MeSH terms

  • Animals
  • Benzoates / chemical synthesis*
  • Benzoates / pharmacokinetics
  • Benzoates / pharmacology*
  • Binding Sites
  • Crystallography, X-Ray
  • Humans
  • Inhibitory Concentration 50
  • Matrix Metalloproteinase 13 / drug effects*
  • Matrix Metalloproteinase Inhibitors / chemical synthesis*
  • Matrix Metalloproteinase Inhibitors / pharmacokinetics
  • Matrix Metalloproteinase Inhibitors / pharmacology*
  • Osteoarthritis / drug therapy
  • Quinazolines / chemical synthesis*
  • Quinazolines / pharmacokinetics
  • Quinazolines / pharmacology*
  • Rats
  • Structure-Activity Relationship

Substances

  • 4-(2-((6-fluoro-2-((((3-(methyloxy)phenyl)methyl)amino)carbonyl)-4-oxo-3,4-dihydroquinazolin-5-yl)oxy)ethyl)benzoic acid
  • Benzoates
  • Matrix Metalloproteinase Inhibitors
  • Quinazolines
  • Matrix Metalloproteinase 13

Associated data

  • PDB/3WV1
  • PDB/3WV2