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

• Published in: European journal of pharmacology 2004-06, Vol.493 (1), p.173-176
• Main Authors: Sakaguchi, Masato, Takai, Shinji, Jin, Denan, Okamoto, Yukiko, Muramatsu, Michiko, Kim, Shokei, Miyazaki, Mizuo
• Format: Article
• Language: English
• Subjects: Acetamides - administration & dosage; Acetamides - pharmacokinetics; Acetamides - therapeutic use; Administration, Oral; Animals; Biological and medical sciences; Bleomycin - adverse effects; Chymase inhibitor; 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; Fibrosis; Japan; Lung; Lung - chemistry; Lung - drug effects; Lung - enzymology; Male; Medical sciences; Pharmacology. Drug treatments; 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; Transforming growth factor-β
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2004.04.024

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.