A selective matrix metalloprotease 12 inhibitor for potential treatment of chronic obstructive pulmonary disease (COPD): discovery of (S)-2-(8-(methoxycarbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid (MMP408)

J Med Chem. 2009 Apr 9;52(7):1799-802. doi: 10.1021/jm900093d.

Abstract

Matrix metalloprotease 12 plays a significant role in airway inflammation and remodeling. Increased expression and production of MMP-12 have been found in the lung of human COPD patients. MMP408 (14), a potent and selective MMP-12 inhibitor, was derived from a potent matrix metalloprotease 2 and 13 inhibitor via lead optimization and has good physical properties and bioavailability. The compound blocks rhMMP-12-induced lung inflammation in a mouse model and was advanced for further development for the treatment of COPD.

MeSH terms

  • Animals
  • Benzofurans / chemical synthesis*
  • Benzofurans / pharmacokinetics
  • Benzofurans / pharmacology
  • Biological Availability
  • Haplorhini
  • Humans
  • In Vitro Techniques
  • Matrix Metalloproteinase Inhibitors*
  • Mice
  • Mice, Inbred C57BL
  • Models, Molecular
  • Pneumonia / chemically induced
  • Pneumonia / drug therapy
  • Pulmonary Disease, Chronic Obstructive / drug therapy*
  • Rats
  • Recombinant Proteins
  • Sheep
  • Species Specificity
  • Stereoisomerism
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / pharmacokinetics
  • Sulfonamides / pharmacology

Substances

  • 2-(8-(methoxycarbonylamino)dibenzo(b,d)furan-3-sulfonamido)-3-methylbutanoic acid
  • Benzofurans
  • Matrix Metalloproteinase Inhibitors
  • Recombinant Proteins
  • Sulfonamides