A specific 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), suppresses development of abdominal aortic aneurysm in hamsters.

Abstract

In this study, we investigated the effect of a specific 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), in the development of abdominal aortic aneurysm in a hamster experimental model. The abdominal aortic aneurysm was induced by application of elastase onto the abdominal aorta in hamster. Each hamster was administered NK3201 (30 mg/kg/day p.o.) or placebo beginning 4 days before application of elastase and continuing through the experiments. Sham-operated hamsters received saline application onto the abdominal aorta. Two weeks after application of elastase, the aortic diameter in the placebo-treated group was significantly increased to 1.6-fold compared with the value for the sham-operated group, whereas that in the NK3201-treated group was significantly reduced. The chymase activities in the sham-operated and the placebo-treated groups were 0.35 +/- 0.01 and 3.44 +/- 0.62 mU/mg protein, respectively, and this difference was significant. NK3201 significantly reduced the chymase activity in the placebo-treated group. Here, we demonstrated for the first time that a chymase inhibitor prevented the development of abdominal aortic aneurysm in a hamster experimental model.

• Authors: Koutaro Tsunemi, Shinji Takai, Masayoshi Nishimoto, Denan Jin, Masato Sakaguchi, Michiko Muramatsu, Atsushi Yuda, Shinjiro Sasaki, Mizuo Miyazaki
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 309 Issue 3 Pg. 879-83 (Jun 2004) ISSN: 0022-3565 [Print] United States
• PMID: 14960660 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Acetamides
• Enzyme Inhibitors
• NK3201
• Pyrimidines
• Serine Endopeptidases
• Pancreatic Elastase
• Chymases

Topics

• Acetamides (therapeutic use)
• Animals
• Aorta (drug effects, pathology)
• Aortic Aneurysm, Abdominal (pathology, prevention & control)
• Chymases
• Cricetinae
• Disease Models, Animal
• Enzyme Inhibitors (therapeutic use)
• Male
• Pancreatic Elastase (metabolism)
• Pyrimidines (therapeutic use)
• Serine Endopeptidases (drug effects, metabolism)