Identification
- Summary
Sacubitril is a neprilysin inhibitor used in combination with valsartan as an adjunct to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction.
- Brand Names
- Entresto
- Generic Name
- Sacubitril
- DrugBank Accession Number
- DB09292
- Background
Sacubitril is a prodrug neprilysin inhibitor used in combination with valsartan to reduce the risk of cardiovascular events in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction. It was approved by the FDA after being given the status of priority review for on July 7, 2015.
Sacubitril's active metabolite, LBQ657 inhibits neprilysin, a neutral endopeptidase that would typically cleave natiuretic peptides such as atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and c-type natriuretic peptide (CNP). ANP and BNP are released under atrial and ventricle stress, which activate downstream receptors leading to vasodilation, natriuresis and diuresis. Under normal conditions, neprilysin breaks down other vasodilating peptides and also vasoconstrictors such as angiotensin I and II, endothelin-1 and peptide amyloid beta-protein. Inhibition of neprilysin therefore leads to reduced breakdown and increased concentration of endogenous natriuretic peptides in addition to increased levels of vasoconstricting hormones such as angiotensin II.
- Type
- Small Molecule
- Groups
- Approved
- Structure
Structure for Sacubitril (DB09292)
- Weight
- Average: 411.498
Monoisotopic: 411.204573038 - Chemical Formula
- C24H29NO5
- Synonyms
- Sacubitril
- Sacubitrilo
- External IDs
- AHU 377
- AHU-377
- AHU377
- LCZ-696
- LCZ696
Pharmacology
- Indication
Used in combination with valsartan to reduce the risk of cardiovascular events in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction. It is usually administered in conjunction with other heart failure therapies, in place of an ACE inhibitor or other ARB.
It is also used in combination with valsartan.4
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- Contraindications & Blackbox Warnings
Avoid life-threatening adverse drug eventsImprove clinical decision support with information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events & improve clinical decision support.- Pharmacodynamics
n a 7-day valsartan-controlled study in patients with reduced ejection fraction (HFrEF), administration of sacubitril + valsartan (Entresto) resulted in a significant non-sustained increase in natriuresis, increased urine cGMP, and decreased plasma MR-proANP and NT-proBNP compared to valsartan. In a 21-day study in HFrEF patients, it significantly increased urine ANP and cGMP and plasma cGMP, and decreased plasma NT-proBNP, aldosterone and endothelin-1. In clinical studies, this combination had no effect on QTc interval.
- Mechanism of action
Sacubitril's active metabolite, LBQ657 inhibits neprilysin, a neutral endopeptidase that would typically cleave natiuretic peptides, which includes: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and c-type natriuretic peptide (CNP). ANP and BNP are released under atrial and ventricle stress, which activate downstream receptors leading to vasodilation, natriuresis and diuresis. Under normal conditions, neprilysin breaks down other vasodilating peptides and also vasoconstrictors such as angiotensin I and II, endothelin-1 and peptide amyloid beta-protein. Therefore, the inhibition of neprilysin leads to reduced breakdown and increased concentration of endogenous natriuretic peptides in addition to increased levels of vasoconstricting hormones such as angiotensin II. (However, when combined with valsartan, would result in blocking of angiotensin II to its receptor, preventing the vasoconstrictive effects and resulting in a decrease in vascular resistance and blood pressure.) Cardiovascular and renal effects of sacubitril is a result of the increased levels of peptides that are normally degraded by neprilysin.
Target Actions Organism ANeprilysin antagonistinhibitorHumans - Absorption
Peak plasma concentrations of sacubitril and it's metabolite, LBQ657 are reached in 0.5 hours and 2 hours respectively. Food does not clinically affect the systemic exposure of sacubitril or LBQ657. The oral bioavailability of sacubitril is >60%. It should be noted that the valsartan found in this combination is more bioavailable than other market available valsartan.
- Volume of distribution
103 L
- Protein binding
Sacubitril and it's metabolite, LBQ657 are highly bound to plasma protein (94-97%).
- Metabolism
Sacubitril is metabolized to LBQ657 by esterases. A low concentration (<10%) of a hydroxyl metabolite has been identified in plasma.
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- Route of elimination
52% to 68% of sacubitril (primarily as the active metabolite LBQ657) is excreted in urine. 37% to 48% of sacubitril (primarily as LBQ657) is excreted in feces
- Half-life
The half life of sacubitril is 1.1 to 3.6 hours, and the half life of it's metabolite LBQ657 is 9.9 to 11.1 hours.
- Clearance
Not Available
- Adverse Effects
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The most common adverse reactions (≥5%) are hypotension, hyperkalemia, cough, dizziness, and renal failure.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbacavir Abacavir may decrease the excretion rate of Sacubitril which could result in a higher serum level. Abaloparatide The risk or severity of adverse effects can be increased when Abaloparatide is combined with Sacubitril. Acebutolol The risk or severity of adverse effects can be increased when Acebutolol is combined with Sacubitril. Aceclofenac Aceclofenac may decrease the excretion rate of Sacubitril which could result in a higher serum level. Acemetacin Acemetacin may decrease the excretion rate of Sacubitril which could result in a higher serum level. Acetaminophen Acetaminophen may decrease the excretion rate of Sacubitril which could result in a higher serum level. Acetazolamide Acetazolamide may increase the excretion rate of Sacubitril which could result in a lower serum level and potentially a reduction in efficacy. Acetylsalicylic acid The risk or severity of angioedema can be increased when Acetylsalicylic acid is combined with Sacubitril. Aclidinium Aclidinium may decrease the excretion rate of Sacubitril which could result in a higher serum level. Acrivastine Sacubitril may decrease the excretion rate of Acrivastine which could result in a higher serum level. 
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- No interactions found.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Active Moieties
Name Kind UNII CAS InChI Key Sacubitrilat prodrug SPI5PBF81S 149709-44-4 DOBNVUFHFMVMDB-BEFAXECRSA-N - Mixture Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image Entresto Sacubitril (49 mg) + Valsartan (51 mg) Tablet Oral Novartis 2015-11-13 Not applicable Canada 
Entresto Sacubitril (49 mg) + Valsartan (51 mg) Tablet, film coated Oral Novartis Europharm Limited 2016-09-08 Not applicable EU 
Entresto Sacubitril (97 mg) + Valsartan (103 mg) Tablet, film coated Oral Novartis Europharm Limited 2016-09-08 Not applicable EU Entresto Sacubitril (24 mg) + Valsartan (26 mg) Tablet, film coated Oral Novartis Europharm Limited 2016-09-08 Not applicable EU Entresto Sacubitril (49 mg) + Valsartan (51 mg) Tablet, film coated Oral Novartis Europharm Limited 2016-09-08 Not applicable EU Entresto Sacubitril (24 mg) + Valsartan (26 mg) Tablet, film coated Oral Novartis Europharm Limited 2016-09-08 Not applicable EU Entresto Sacubitril (97 mg) + Valsartan (103 mg) Tablet, film coated Oral Novartis Europharm Limited 2016-09-08 Not applicable EU Entresto Sacubitril (49 mg) + Valsartan (51 mg) Tablet, film coated Oral Novartis Europharm Limited 2020-12-16 Not applicable EU Entresto Sacubitril (24 mg/1) + Valsartan (26 mg/1) Tablet, film coated Oral Novartis Pharmaceuticals Corporation 2015-07-07 Not applicable US 
Entresto Sacubitril (49 mg) + Valsartan (51 mg) Tablet, film coated Oral Novartis Europharm Limited 2016-09-08 Not applicable EU
Categories
- ATC Codes
- C09DX04 — Valsartan and sacubitril
- Drug Categories
- Acids, Acyclic
- Agents causing angioedema
- Amino Acids
- Amino Acids, Branched-Chain
- Amino Acids, Essential
- Amino Acids, Peptides, and Proteins
- Benzene Derivatives
- Butyrates
- Drugs that are Mainly Renally Excreted
- Hypotensive Agents
- Neprilysin Inhibitor
- Neprilysin, antagonists & inhibitors
- OATP1B1/SLCO1B1 Inhibitors
- OATP1B3 inhibitors
- Pharmaceutical Preparations
- Tetrazoles
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as biphenyls and derivatives. These are organic compounds containing to benzene rings linked together by a C-C bond.
- Kingdom
- Organic compounds
- Super Class
- Benzenoids
- Class
- Benzene and substituted derivatives
- Sub Class
- Biphenyls and derivatives
- Direct Parent
- Biphenyls and derivatives
- Alternative Parents
- Gamma amino acids and derivatives / Amphetamines and derivatives / Fatty acid esters / N-acyl amines / Dicarboxylic acids and derivatives / Secondary carboxylic acid amides / Carboxylic acid esters / Carboxylic acids / Organopnictogen compounds / Organonitrogen compounds show 3 more
- Substituents
- Amphetamine or derivatives / Aromatic homomonocyclic compound / Biphenyl / Carbonyl group / Carboxamide group / Carboxylic acid / Carboxylic acid derivative / Carboxylic acid ester / Dicarboxylic acid or derivatives / Fatty acid ester show 12 more
- Molecular Framework
- Aromatic homomonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- 17ERJ0MKGI
- CAS number
- 149709-62-6
- InChI Key
- PYNXFZCZUAOOQC-UTKZUKDTSA-N
- InChI
- InChI=1S/C24H29NO5/c1-3-30-24(29)17(2)15-21(25-22(26)13-14-23(27)28)16-18-9-11-20(12-10-18)19-7-5-4-6-8-19/h4-12,17,21H,3,13-16H2,1-2H3,(H,25,26)(H,27,28)/t17-,21+/m1/s1
- IUPAC Name
- 3-{[(2S,4R)-1-{[1,1'-biphenyl]-4-yl}-5-ethoxy-4-methyl-5-oxopentan-2-yl]carbamoyl}propanoic acid
- SMILES
- CCOC(=O)[C@H](C)C[C@@H](CC1=CC=C(C=C1)C1=CC=CC=C1)NC(=O)CCC(O)=O
References
- General References
- Gu J, Noe A, Chandra P, Al-Fayoumi S, Ligueros-Saylan M, Sarangapani R, Maahs S, Ksander G, Rigel DF, Jeng AY, Lin TH, Zheng W, Dole WP: Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi). J Clin Pharmacol. 2010 Apr;50(4):401-14. doi: 10.1177/0091270009343932. Epub 2009 Nov 23. [Article]
- Mills J, Vardeny O: The Role of Neprilysin Inhibitors in Cardiovascular Disease. Curr Heart Fail Rep. 2015 Dec;12(6):389-94. doi: 10.1007/s11897-015-0270-8. [Article]
- King JB, Bress AP, Reese AD, Munger MA: Neprilysin Inhibition in Heart Failure with Reduced Ejection Fraction: A Clinical Review. Pharmacotherapy. 2015 Sep;35(9):823-37. doi: 10.1002/phar.1629. [Article]
- FDA Approved Drug Products: ENTRESTO (sacubitril and valsartan) tablets [Link]
- External Links
- KEGG Drug
- D10225
- PubChem Compound
- 9811834
- PubChem Substance
- 310265184
- ChemSpider
- 7987587
- 1656328
- ChEBI
- 134714
- ChEMBL
- CHEMBL3137301
- ZINC
- ZINC000003792417
- PharmGKB
- PA166131580
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Sacubitril
- FDA label
- Download (1.28 MB)
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 4 Active Not Recruiting Basic Science Hypertension 1 4 Completed Other Chronic Heart Failure (CHF) / Sleep Apnea 1 4 Completed Other Heart Failure 1 4 Completed Other Hearth Failure With Reduced Ejection Fraction (HFrEF) 1 4 Completed Supportive Care Acute Heart Failure (AHF) 1 4 Completed Supportive Care Hearth Failure With Reduced Ejection Fraction (HFrEF) 2 4 Completed Treatment Bodycomposition / Exercise Tolerance / Heart Failure / Strength, Muscle / Vasodilation 1 4 Completed Treatment Chronic Heart Failure With Reduced Ejection Fraction (HFrEF) 1 4 Completed Treatment Diabetes / Heart Failure 1 4 Completed Treatment Heart Failure 5
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet Oral Tablet, film coated Oral Tablet, coated Oral - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US8796331 Yes 2014-08-05 2023-07-14 US US8101659 Yes 2012-01-24 2023-07-14 US US7468390 Yes 2008-12-23 2024-05-27 US US8404744 Yes 2013-03-26 2023-07-14 US US8877938 Yes 2014-11-04 2027-11-27 US US9388134 Yes 2016-07-12 2027-05-08 US US9517226 No 2016-12-13 2033-08-22 US US9937143 No 2018-04-10 2033-08-22 US US11058667 No 2021-07-13 2036-05-09 US US11135192 No 2021-10-05 2033-08-22 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.000942 mg/mL ALOGPS logP 3.9 ALOGPS logP 3.79 Chemaxon logS -5.6 ALOGPS pKa (Strongest Acidic) 4.18 Chemaxon pKa (Strongest Basic) -1.6 Chemaxon Physiological Charge -1 Chemaxon Hydrogen Acceptor Count 4 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 92.7 Å2 Chemaxon Rotatable Bond Count 12 Chemaxon Refractivity 114.06 m3·mol-1 Chemaxon Polarizability 44.48 Å3 Chemaxon Number of Rings 2 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS Not Available
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- AntagonistInhibitor
- General Function
- Zinc ion binding
- Specific Function
- Thermolysin-like specificity, but is almost confined on acting on polypeptides of up to 30 amino acids (PubMed:15283675, PubMed:8168535). Biologically important in the destruction of opioid peptide...
- Gene Name
- MME
- Uniprot ID
- P08473
- Uniprot Name
- Neprilysin
- Molecular Weight
- 85513.225 Da
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Sodium-independent organic anion transmembrane transporter activity
- Specific Function
- Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
- Gene Name
- SLCO1B1
- Uniprot ID
- Q9Y6L6
- Uniprot Name
- Solute carrier organic anion transporter family member 1B1
- Molecular Weight
- 76447.99 Da
References
- Mills J, Vardeny O: The Role of Neprilysin Inhibitors in Cardiovascular Disease. Curr Heart Fail Rep. 2015 Dec;12(6):389-94. doi: 10.1007/s11897-015-0270-8. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Sodium-independent organic anion transmembrane transporter activity
- Specific Function
- Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotre...
- Gene Name
- SLCO1B3
- Uniprot ID
- Q9NPD5
- Uniprot Name
- Solute carrier organic anion transporter family member 1B3
- Molecular Weight
- 77402.175 Da
References
- Mills J, Vardeny O: The Role of Neprilysin Inhibitors in Cardiovascular Disease. Curr Heart Fail Rep. 2015 Dec;12(6):389-94. doi: 10.1007/s11897-015-0270-8. [Article]
Drug created at October 29, 2015 21:43 / Updated at March 24, 2022 01:23