Dicarboxylic Acid Dipeptide Neutral Endopeptidase Inhibitors

Ksander, Gary M.; Ghai, R. D.; deJesus, Reynalda; Diefenbacher, Clive; Yuan, Andrew; Berry, Carol; Sakane, Yumi; Trapani, Angelo J.

doi:10.1021/jm00010a014

Cited by 66 publications

(56 citation statements)

References 5 publications

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“…LCZ696, a first-in-class ARNI, comprises molecular moieties of valsartan, a well-established ARB [204] and of the NEP inhibitor prodrug sacubitril (AHU377), which is metabolized to the active NEP inhibitor LBQ657 by enzymatic cleavage of its ethyl ester [205]. LCZ696 is a novel single molecule in which the molecular moieties of valsartan and the molecular moieties of AHU377 are present in a 1:1 molar ratio.…”

Section: Exploring Pharmacological Approaches To Enhance Natriuretic mentioning

confidence: 99%

The natriuretic peptides system in the pathophysiology of heart failure: from molecular basis to treatment

Carnovali²,

2015

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Section: Exploring Pharmacological Approaches To Enhance Natriuretic mentioning

confidence: 99%

The natriuretic peptides system in the pathophysiology of heart failure: from molecular basis to treatment

Carnovali²,

2015

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“…1), a potent neprilysin inhibitor, to produce its intended pharmacological effects (Ksander et al, 1995). Thus, it is plausible to speculate that patients who cannot efficiently activate sacubitril may respond poorly to the treatment.…”

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confidence: 99%

Sacubitril Is Selectively Activated by Carboxylesterase 1 (CES1) in the Liver and the Activation Is Affected by CES1 Genetic Variation

Shi

Wang

Nguyen

et al. 2016

Drug Metabolism and Disposition

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Sacubitril was recently approved by the Food and Drug Administration for use in combination with valsartan for the treatment of patients with heart failure with reduced ejection fraction. As a prodrug, sacubitril must be metabolized (hydrolyzed) to its active metabolite sacubitrilat (LBQ657) to exert its intended therapeutic effects. Thus, understanding the determinants of sacubitril activation will lead to the improvement of sacubitril pharmacotherapy. The objective of this study was to identify the enzyme(s) responsible for the activation of sacubitril, and determine the impact of genetic variation on sacubitril activation. First, an incubation study of sacubitril with human plasma and the S9 fractions of human liver, intestine, and kidney was conducted. Sacubitril was found to be activated by human liver S9 fractions only. Moreover, sacubitril activation was significantly inhibited by the carboxylesterase 1 (CES1) inhibitor bis-(p-nitrophenyl) phosphate in human liver S9. Further incubation studies with recombinant human CES1 and carboxylesterase 2 confirmed that sacubitril is a selective CES1 substrate. The in vitro study of cell lines transfected with wildtype CES1 and the CES1 variant G143E (rs71647871) demonstrated that G143E is a loss-of-function variant for sacubitril activation. Importantly, sacubitril activation was significantly impaired in human livers carrying the G143E variant. In conclusion, sacubitril is selectively activated by CES1 in human liver. The CES1 genetic variant G143E can significantly impair sacubitril activation. Therefore, CES1 genetic variants appear to be an important contributing factor to interindividual variability in sacubitril activation, and have the potential to serve as biomarkers to optimize sacubitril pharmacotherapy.

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“…It is synthesized by dissolution of the two drugs followed by the addition of aqueous sodium hydroxide solution to induce crystallization. 37, 38 Crystal valsartan/sacubitril contains six sacubitril and six valsartan moieties in their anionic forms, 18 penta- and hexa- coordinated sodium cations, and 15 water molecules, and has been described as a sodium supramolecular complex. 38 After ingestion, valsartan/sacubitril dissociates to valsartan and sacubitril, which is further converted by esterases to the active inhibitor of neprilysin LBQ657.…”

Section: Pharmacokinetics Of Valsartan/sacubitrilmentioning

confidence: 99%

Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition

2016

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Heart failure affects approximately 5.7 million people in the United States alone. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and aldosterone antagonists have improved mortality in patients with heart failure and reduced ejection fraction, but mortality remains high. In July 2015, the FDA approved the first of a new class of drugs for the treatment of heart failure; valsartan/sacubitril (formerly known as LCZ696 and currently marketed by Novartis as Entresto) combines the angiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug sacubitril in a 1:1 ratio in a sodium supramolecular complex. Sacubitril is converted by esterases to LBQ657, which inhibits neprilysin, the enzyme responsible for the degradation of the natriuretic peptides and many other vasoactive peptides. Thus, this combined angiotensin receptor antagonist and neprilysin inhibitor addresses two of the pathophysiologic mechanisms of heart failure - activation of the renin-angiotensin-aldosterone system and decreased sensitivity to natriuretic peptides. In the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) trial, valsartan/sacubitril significantly reduced mortality and hospitalization for heart failure, as well as blood pressure, compared to enalapril in patients with heart failure, reduced ejection fraction, and an elevated circulating level of brain natriuretic peptide or N-terminal pro-brain natriuretic peptide. Ongoing clinical trials are evaluating the role of valsartan/sacubitril in the treatment of heart failure with preserved ejection fraction and hypertension. We review here the mechanisms of action of valsartan/sacubitril, the pharmacologic properties of the drug, and its efficacy and safety in the treatment of heart failure and hypertension.

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Dicarboxylic Acid Dipeptide Neutral Endopeptidase Inhibitors

Cited by 66 publications

References 5 publications

The natriuretic peptides system in the pathophysiology of heart failure: from molecular basis to treatment

The natriuretic peptides system in the pathophysiology of heart failure: from molecular basis to treatment

Sacubitril Is Selectively Activated by Carboxylesterase 1 (CES1) in the Liver and the Activation Is Affected by CES1 Genetic Variation

Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition

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