Identification of an orally efficacious matrix metalloprotease 12 inhibitor for potential treatment of asthma

J Med Chem. 2009 Sep 10;52(17):5408-19. doi: 10.1021/jm900809r.

Abstract

MMP-12 plays a significant role in airway inflammation and remodeling. Increased expression and production of MMP-12 have been observed in the lungs of asthmatic patients. Compound 27 was identified as a potent and selective MMP-12 inhibitor possessing good physicochemical properties. In pharmacological studies, the compound was orally efficacious in an MMP-12 induced ear-swelling inflammation model in the mouse with a good dose response. This compound also exhibited oral efficacy in a naturally Ascaris-sensitized sheep asthma model showing significant inhibition of the late phase response to allergen challenge. This compound has been considered for further development as a treatment therapy for asthma.

MeSH terms

  • Administration, Oral
  • Animals
  • Asthma / drug therapy*
  • Asthma / enzymology
  • Drug Discovery
  • Female
  • Humans
  • Inhibitory Concentration 50
  • Matrix Metalloproteinase Inhibitors*
  • Mice
  • Protease Inhibitors / administration & dosage*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*
  • Protease Inhibitors / therapeutic use
  • Rats
  • Sheep
  • Structure-Activity Relationship

Substances

  • Matrix Metalloproteinase Inhibitors
  • Protease Inhibitors