Sacubitril

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
Thumb
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.

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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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.

TargetActionsOrganism
ANeprilysin
antagonist
inhibitor
Humans
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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Toxicity

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.
DrugInteraction
AbacavirAbacavir may decrease the excretion rate of Sacubitril which could result in a higher serum level.
AcebutololThe risk or severity of adverse effects can be increased when Sacubitril is combined with Acebutolol.
AceclofenacAceclofenac may decrease the excretion rate of Sacubitril which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Sacubitril which could result in a higher serum level.
AcetaminophenAcetaminophen may decrease the excretion rate of Sacubitril which could result in a higher serum level.
AcetazolamideAcetazolamide may increase the excretion rate of Sacubitril which could result in a lower serum level and potentially a reduction in efficacy.
Acetylsalicylic acidThe risk or severity of angioedema can be increased when Acetylsalicylic acid is combined with Sacubitril.
AclidiniumAclidinium may decrease the excretion rate of Sacubitril which could result in a higher serum level.
AcrivastineSacubitril may decrease the excretion rate of Acrivastine which could result in a higher serum level.
AcyclovirAcyclovir may decrease the excretion rate of Sacubitril which could result in a higher serum level.
Interactions
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Food Interactions
No interactions found.

Products

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Active Moieties
NameKindUNIICASInChI Key
SacubitrilatprodrugSPI5PBF81S149709-44-4DOBNVUFHFMVMDB-BEFAXECRSA-N
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
EntrestoSacubitril (49 mg) + Valsartan (51 mg)Tablet, film coatedOralNovartis Europharm Limited2020-12-16Not applicableEU flag
EntrestoSacubitril (24 mg) + Valsartan (26 mg)Tablet, film coatedOralNovartis Europharm Limited2016-09-08Not applicableEU flag
EntrestoSacubitril (49 mg) + Valsartan (51 mg)Tablet, film coatedOralNovartis Europharm Limited2016-09-08Not applicableEU flag
EntrestoSacubitril (97 mg) + Valsartan (103 mg)Tablet, film coatedOralNovartis Europharm Limited2016-09-08Not applicableEU flag
EntrestoSacubitril (24 mg) + Valsartan (26 mg)Tablet, film coatedOralNovartis Europharm Limited2020-12-16Not applicableEU flag
EntrestoSacubitril (97 mg) + Valsartan (103 mg)TabletOralNovartis2015-11-13Not applicableCanada flag
EntrestoSacubitril (97 mg) + Valsartan (103 mg)Tablet, film coatedOralNovartis Europharm Limited2016-09-08Not applicableEU flag
EntrestoSacubitril (97 mg) + Valsartan (103 mg)Tablet, film coatedOralNovartis Europharm Limited2020-12-16Not applicableEU flag
EntrestoSacubitril (49 mg) + Valsartan (51 mg)Tablet, film coatedOralNovartis Europharm Limited2016-09-08Not applicableEU flag
EntrestoSacubitril (49 mg/1) + Valsartan (51 mg/1)Tablet, film coatedOralNovartis Pharmaceuticals Corporation2015-07-07Not applicableUS flag

Categories

ATC Codes
C09DX04 — Valsartan and sacubitril
Drug Categories
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
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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
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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
  1. 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]
  2. 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]
  3. 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]
KEGG Drug
D10225
PubChem Compound
9811834
PubChem Substance
310265184
ChemSpider
7987587
RxNav
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
PhaseStatusPurposeConditionsCount
4Active Not RecruitingBasic ScienceHigh Blood Pressure (Hypertension)1
4CompletedOtherChronic Heart Failure (CHF) / Sleep Apnea1
4CompletedOtherHeart Failure1
4CompletedOtherHeart Failure With Reduced Ejection Fraction (HFrEF)1
4CompletedSupportive CareAcute Heart Failure (AHF)1
4CompletedSupportive CareHeart Failure With Reduced Ejection Fraction (HFrEF)1
4CompletedSupportive CareHearth Failure With Reduced Ejection Fraction (HFrEF)1
4CompletedTreatmentBodycomposition / Exercise Tolerance / Heart Failure / Strength, Muscle / Vasodilation1
4CompletedTreatmentChronic Heart Failure With Reduced Ejection Fraction (HFrEF)1
4CompletedTreatmentDiabetes / Heart Failure1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral
Tablet, film coatedOral
Tablet, coatedOral
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8796331Yes2014-08-052023-07-14US flag
US8101659Yes2012-01-242023-07-14US flag
US7468390Yes2008-12-232024-05-27US flag
US8404744Yes2013-03-262023-07-14US flag
US8877938Yes2014-11-042027-11-27US flag
US9388134Yes2016-07-122027-05-08US flag
US9517226No2013-08-222033-08-22US flag
US9937143No2013-08-222033-08-22US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.000942 mg/mLALOGPS
logP3.9ALOGPS
logP3.79ChemAxon
logS-5.6ALOGPS
pKa (Strongest Acidic)4.18ChemAxon
pKa (Strongest Basic)-1.6ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area92.7 Å2ChemAxon
Rotatable Bond Count12ChemAxon
Refractivity114.06 m3·mol-1ChemAxon
Polarizability44.48 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

Drugtargets
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
Inhibitor
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
  1. 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
  1. 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 on October 29, 2015 21:43 / Updated on February 21, 2021 18:52