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

doi:10.1124/JPET.103.063974

Paper

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

Published Jun 1, 2004 · Koutaro Tsunemi, S. Takai, M. Nishimoto

Journal of Pharmacology and Experimental Therapeutics

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54

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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.

RCT

Animal Study

Study Snapshot

NK3201 effectively prevents abdominal aortic aneurysm development in a hamster experimental model, suggesting potential therapeutic applications for treating abdominal aortic aneurysm.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

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

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References

Application of a chymase inhibitor, NK3201, for prevention of vascular proliferation.

NK3201 effectively prevents vascular proliferation without affecting blood pressure, as local angiotensin II production by chymase is involved only in vascular proliferation.

A Novel Chymase Inhibitor, 4-[1-{[bis-(4-Methyl-phenyl)-methyl]-carbamoyl}-3-(2-ethoxy-benzyl)-4-oxo-azetidine-2-yloxy]-benzoic acid (BCEAB), Suppressed Cardiac Fibrosis in Cardiomyopathic Hamsters

The novel chymase inhibitor BCEAB significantly reduces cardiac chymase activity and improves cardiac function in cardiomyopathic hamsters, suggesting its potential as a treatment for cardiomyopathy.

Impact of chymase inhibitor on cardiac function and survival after myocardial infarction.

NK3201 treatment improves cardiac function and reduces mortality rate after myocardial infarction in hamsters, offering a potential novel therapeutic target in post-MI treatment.

A Novel 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 Intimal Hyperplasia after Balloon Injury

NK3201 effectively prevents intimal hyperplasia in carotid arteries injured by a balloon catheter in dogs.

Development of the chymase inhibitor as an anti-tissue-remodeling drug: myocardial infarction and some other possibilities.

Orally active chymase inhibitor NK3201 shows potential in inhibiting tissue remodeling in diseases like myocardial infarction and pulmonary fibrosis by promoting inflammation, angiotensin II formation, and fibrosis.

Citations

Is chymase 1 a therapeutic target in cardiovascular disease?

Chymase 1 plays a critical role in the pathogenesis of cardiovascular disease and heart failure, but its potential therapeutic benefits in humans have not been fully recognized due to limitations in clinical trials.

Multiple Tumor-Associated Intracranial Aneurysms Adjacent to a Suprasellar Germ Cell Tumor: Case Report and Review of Literature

Multiple intracranial aneurysms associated with suprasellar germ cell tumors are rare and require complex multidisciplinary treatment.

Mechanism of Albuminuria Reduction by Chymase Inhibition in Diabetic Mice

Chymase inhibition reduces albuminuria in diabetic mice by attenuating podocyte injury caused by oxidative stress.

Therapeutic Potential of Chymase Inhibitors in Cardiovascular Diseases: An Overview

Chymase inhibitors show potential as a therapeutic approach for managing cardiovascular diseases like atherosclerosis, hypertension, vascular proliferation, myocardial infarction, and heart failure by inactivating the local renin-angiotensin system.

Novel Insight into the in vivo Function of Mast Cell Chymase: Lessons from Knockouts and Inhibitors

Mast cell chymase plays a crucial role in various pathologies, with potential as a promising drug target and also playing protective and homeostatic roles.

Pathogenic mechanisms and the potential of drug therapies for aortic aneurysm.

This review highlights novel contributors to aortic aneurysm formation and progression, and highlights ongoing clinical trials focusing on therapeutic strategies to slow aneurysm growth.

Multifunctional Role of Chymase in Acute and Chronic Tissue Injury and Remodeling.

Chymase plays a multifunctional role in tissue injury and remodeling, explaining the residual risk in cardiovascular disease trials using conventional renin-angiotensin system blockade.

Bidirectional Mast Cell–Eosinophil Interactions in Inflammatory Disorders and Cancer

Bidirectional interactions between mast cells and eosinophils may play a crucial role in allergic disorders, autoimmune disorders, cardiovascular diseases, and cancer.

Increased Bone Mass in Female Mice Lacking Mast Cell Chymase

Mast cell chymase, which regulates bone homeostasis, is involved in increased bone mass in female mice, but does not protect against osteoporosis.