Combined neprilysin and renin-angiotensin system inhibition for the treatment of heart failure.

Abstract

Neprilysin is an enzyme that contributes to the breakdown of the biologically active natriuretic peptides and several other vasoactive compounds. Inhibiting neprilysin has been a therapeutic target for several compounds that have been tested in cardiovascular disease, including ecadotril, candoxatril, omapatrilat, and LCZ696. Although ecadotril, candoxatril, and omapatrilat were initially tested in hypertension and/or heart failure, lack of efficacy and side effects led to discontinuation of their development. LCZ696 (sacubitril valsartan) is a first-in-class angiotensin receptor neprilysin inhibitor that has been developed for use in heart failure. This compound is composed of 2 molecular moieties in a single crystalline complex-the angiotensin receptor blocker valsartan and a neprilysin inhibitor prodrug-and has now been tested in hypertension, in a phase 2 trial in heart failure with preserved ejection fraction, and has demonstrated greater efficacy than enalapril in a phase 3 trial in heart failure with reduced ejection fraction. Its ability to inhibit the renin-angiotensin-aldosterone axis and augment the endogenous natriuretic peptide system provides a distinctive mechanism of action in cardiovascular disease.

• Authors: Orly Vardeny, Ryan Miller, Scott D Solomon
• Journal: JACC. Heart failure (JACC Heart Fail) Vol. 2 Issue 6 Pg. 663-70 (Dec 2014) ISSN: 2213-1787 [Electronic] United States
• PMID: 25306450 (Publication Type: Journal Article, Review)
• Copyright: Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Chemical References

• Aminobutyrates
• Angiotensin Receptor Antagonists
• Antihypertensive Agents
• Biomarkers
• Biphenyl Compounds
• Drug Combinations
• Peptide Fragments
• Tetrazoles
• pro-brain natriuretic peptide (1-76)
• Natriuretic Peptide, Brain
• Valsartan
• Neprilysin
• sacubitril and valsartan sodium hydrate drug combination

Topics

• Aminobutyrates (therapeutic use)
• Angiotensin Receptor Antagonists (therapeutic use)
• Antihypertensive Agents (therapeutic use)
• Biomarkers (metabolism)
• Biphenyl Compounds
• Clinical Trials as Topic
• Drug Combinations
• Drug Therapy, Combination
• Heart Failure (drug therapy, mortality)
• Humans
• Hypertension (drug therapy, mortality)
• Natriuretic Peptide, Brain (metabolism)
• Neprilysin (antagonists & inhibitors)
• Peptide Fragments (metabolism)
• Renin-Angiotensin System (drug effects)
• Tetrazoles (therapeutic use)
• Valsartan