A specific chymase inhibitor, NK3201, suppresses bleomycin-induced pulmonary fibrosis in hamsters

Eur J Pharmacol. 2004 Jun 16;493(1-3):173-6. doi: 10.1016/j.ejphar.2004.04.024.

Abstract

We evaluated whether a chymase inhibitor, 2-(5-formylamino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-[(3,4-dioxo-1-phenyl-7-(2-pyridyloxy))-2-heptyl]acetamide (NK3201), suppressed bleomycin-induced pulmonary fibrosis. Hamsters were orally administered NK3201 (30 mg/kg per day) or placebo, beginning 5 days before intratracheal instillation of bleomycin (10 mg/kg). Four weeks after the instillation of bleomycin, pulmonary chymase activity in placebo-treated hamsters was significantly higher than in control hamsters, whereas the activity in NK3201-treated hamsters was significantly lower than in placebo-treated hamsters. The ratio of fibrotic area to total area in NK3201-treated hamsters was significantly decreased to 54.0% of the ratio in placebo-treated hamsters. Therefore, NK3201 may be useful in the prevention of pulmonary fibrosis.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetamides / administration & dosage
  • Acetamides / pharmacokinetics*
  • Acetamides / therapeutic use
  • Administration, Oral
  • Animals
  • Bleomycin / adverse effects*
  • Chymases
  • Collagen Type III / drug effects
  • Collagen Type III / genetics
  • Cricetinae
  • Drug Evaluation, Preclinical / methods
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / pharmacokinetics*
  • Enzyme Inhibitors / therapeutic use
  • Japan
  • Lung / chemistry
  • Lung / drug effects
  • Lung / enzymology
  • Male
  • Pulmonary Fibrosis / chemically induced*
  • Pulmonary Fibrosis / pathology
  • Pulmonary Fibrosis / prevention & control
  • Pyrimidines / administration & dosage
  • Pyrimidines / pharmacokinetics*
  • Pyrimidines / therapeutic use
  • RNA, Messenger / chemistry
  • RNA, Messenger / drug effects
  • RNA, Messenger / genetics
  • Serine Endopeptidases / chemistry
  • Serine Endopeptidases / drug effects*
  • Tissue Extracts / chemistry

Substances

  • Acetamides
  • Collagen Type III
  • Enzyme Inhibitors
  • NK3201
  • Pyrimidines
  • RNA, Messenger
  • Tissue Extracts
  • Bleomycin
  • Serine Endopeptidases
  • Chymases