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

J Pharmacol Exp Ther. 2004 Jun;309(3):879-83. doi: 10.1124/jpet.103.063974. Epub 2004 Feb 11.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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