U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ABSOLUTE
Molecular Formula C24H29NO5
Molecular Weight 411.4917
Optical Activity UNSPECIFIED
Defined Stereocenters 2 / 2
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of SACUBITRIL

SMILES

CCOC(=O)[C@]([H])(C)C[C@@]([H])(Cc1ccc(cc1)-c2ccccc2)N=C(CCC(=O)O)O

InChI

InChIKey=PYNXFZCZUAOOQC-UTKZUKDTSA-N
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

HIDE SMILES / InChI

Molecular Formula C24H29NO5
Molecular Weight 411.4917
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 2 / 2
E/Z Centers 0
Optical Activity UNSPECIFIED

Sacubitril is a prodrug neprilysin inhibitor used in combination with valsartan (sold under the brand name Entresto among others) to reduce the risk of cardiovascular events in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction. It was approved under the FDA's priority review process for use in heart failure 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.

CNS Activity

Curator's Comment:: Sacubitril—small amounts cross the blood-brain barrier. Sacubitril is readily converted to LBQ657 by esterases, LBQ657 crosses the blood brain barrier to a limited extent (0.28%).

Originator

Curator's Comment:: # Novartis

Approval Year

Targets

Targets

Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
ENTRESTO

Approved Use

ENTRESTO is a combination of sacubitril, a neprilysin inhibitor, and valsartan, an angiotensin II receptor blocker, indicated 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. (1.1) ENTRESTO is usually administered in conjunction with other heart failure therapies, in place of an ACE inhibitor or other ARB. (1.1) 1.1 Heart Failure ENTRESTO is indicated 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. ENTRESTO is usually administered in conjunction with other heart failure therapies, in place of an ACE inhibitor or other ARB.

Launch Date

1.43622721E12
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
16345 ng/mL
200 mg 2 times / day steady-state, oral
dose: 200 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered: VALSARTAN
SACUBITRILAT plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
9103 ng/mL
100 mg 2 times / day steady-state, oral
dose: 100 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered: VALSARTAN
SACUBITRILAT plasma
Homo sapiens
population: UNKNOWN
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
2408 ng/mL
200 mg 2 times / day steady-state, oral
dose: 200 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered: VALSARTAN
SACUBITRIL plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
1229 ng/mL
100 mg 2 times / day steady-state, oral
dose: 100 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered: VALSARTAN
SACUBITRIL plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
147111 ng × h/mL
200 mg 2 times / day steady-state, oral
dose: 200 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered: VALSARTAN
SACUBITRILAT plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
82633 ng × h/mL
100 mg 2 times / day steady-state, oral
dose: 100 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered: VALSARTAN
SACUBITRILAT plasma
Homo sapiens
population: UNKNOWN
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
3153 ng × h/mL
200 mg 2 times / day steady-state, oral
dose: 200 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered: VALSARTAN
SACUBITRIL plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
1537 ng × h/mL
100 mg 2 times / day steady-state, oral
dose: 100 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered: VALSARTAN
SACUBITRIL plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
18.4 h
200 mg 2 times / day steady-state, oral
dose: 200 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered: VALSARTAN
SACUBITRILAT plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
3.9 h
200 mg 2 times / day steady-state, oral
dose: 200 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered: VALSARTAN
SACUBITRIL plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
194 mg 1 times / day steady, oral
Recommended
Dose: 194 mg, 1 times / day
Route: oral
Route: steady
Dose: 194 mg, 1 times / day
Co-administed with::
valsartan(206 mg/1/day)
Sources:
healthy, 18-65 years
n = 22
Health Status: healthy
Age Group: 18-65 years
Sex: M+F
Population Size: 22
Sources:
Other AEs: Orthostatic hypotension...
Other AEs:
Orthostatic hypotension (13.64%)
Sources:
194 mg 1 times / day steady, oral
Recommended
Dose: 194 mg, 1 times / day
Route: oral
Route: steady
Dose: 194 mg, 1 times / day
Co-administed with::
valsartan(206 mg/1/day)
Sources:
unhealthy, 18-65 years
n = 6
Health Status: unhealthy
Condition: severe renal impairment
Age Group: 18-65 years
Sex: M+F
Population Size: 6
Sources:
Other AEs: Orthostatic hypotension...
Other AEs:
Orthostatic hypotension (50%)
Sources:
194 mg 1 times / day steady, oral
Recommended
Dose: 194 mg, 1 times / day
Route: oral
Route: steady
Dose: 194 mg, 1 times / day
Co-administed with::
valsartan(206 mg/1/day)
Sources:
unhealthy, 18-65 years
n = 8
Health Status: unhealthy
Condition: mild renal impairment
Age Group: 18-65 years
Sex: M+F
Population Size: 8
Sources:
Other AEs: Orthostatic hypotension...
Other AEs:
Orthostatic hypotension (25%)
Sources:
194 mg 1 times / day steady, oral
Recommended
Dose: 194 mg, 1 times / day
Route: oral
Route: steady
Dose: 194 mg, 1 times / day
Co-administed with::
valsartan(206 mg/1/day)
Sources:
unhealthy, 18-65 years
n = 8
Health Status: unhealthy
Condition: moderate renal impairment
Age Group: 18-65 years
Sex: M+F
Population Size: 8
Sources:
Other AEs: Orthostatic hypotension...
Other AEs:
Orthostatic hypotension (62.5%)
Sources:
49 mg 2 times / day multiple, oral
Recommended
Dose: 49 mg, 2 times / day
Route: oral
Route: multiple
Dose: 49 mg, 2 times / day
Co-administed with::
valsartan(51 mg/2/day)
Sources: Page: 6.1
unhealthy, adult
n = 10495
Health Status: unhealthy
Condition: heart failure
Age Group: adult
Sex: unknown
Population Size: 10495
Sources: Page: 6.1
Disc. AE: Kidney dysfunction, Hypotension...
AEs leading to
discontinuation/dose reduction:
Kidney dysfunction (1.8%)
Hypotension (1.7%)
Hyperkalemia (1.3%)
Sources: Page: 6.1
AEs

AEs

AESignificanceDosePopulation
Orthostatic hypotension 13.64%
194 mg 1 times / day steady, oral
Recommended
Dose: 194 mg, 1 times / day
Route: oral
Route: steady
Dose: 194 mg, 1 times / day
Co-administed with::
valsartan(206 mg/1/day)
Sources:
healthy, 18-65 years
n = 22
Health Status: healthy
Age Group: 18-65 years
Sex: M+F
Population Size: 22
Sources:
Orthostatic hypotension 50%
194 mg 1 times / day steady, oral
Recommended
Dose: 194 mg, 1 times / day
Route: oral
Route: steady
Dose: 194 mg, 1 times / day
Co-administed with::
valsartan(206 mg/1/day)
Sources:
unhealthy, 18-65 years
n = 6
Health Status: unhealthy
Condition: severe renal impairment
Age Group: 18-65 years
Sex: M+F
Population Size: 6
Sources:
Orthostatic hypotension 25%
194 mg 1 times / day steady, oral
Recommended
Dose: 194 mg, 1 times / day
Route: oral
Route: steady
Dose: 194 mg, 1 times / day
Co-administed with::
valsartan(206 mg/1/day)
Sources:
unhealthy, 18-65 years
n = 8
Health Status: unhealthy
Condition: mild renal impairment
Age Group: 18-65 years
Sex: M+F
Population Size: 8
Sources:
Orthostatic hypotension 62.5%
194 mg 1 times / day steady, oral
Recommended
Dose: 194 mg, 1 times / day
Route: oral
Route: steady
Dose: 194 mg, 1 times / day
Co-administed with::
valsartan(206 mg/1/day)
Sources:
unhealthy, 18-65 years
n = 8
Health Status: unhealthy
Condition: moderate renal impairment
Age Group: 18-65 years
Sex: M+F
Population Size: 8
Sources:
Hyperkalemia 1.3%
Disc. AE
49 mg 2 times / day multiple, oral
Recommended
Dose: 49 mg, 2 times / day
Route: oral
Route: multiple
Dose: 49 mg, 2 times / day
Co-administed with::
valsartan(51 mg/2/day)
Sources: Page: 6.1
unhealthy, adult
n = 10495
Health Status: unhealthy
Condition: heart failure
Age Group: adult
Sex: unknown
Population Size: 10495
Sources: Page: 6.1
Hypotension 1.7%
Disc. AE
49 mg 2 times / day multiple, oral
Recommended
Dose: 49 mg, 2 times / day
Route: oral
Route: multiple
Dose: 49 mg, 2 times / day
Co-administed with::
valsartan(51 mg/2/day)
Sources: Page: 6.1
unhealthy, adult
n = 10495
Health Status: unhealthy
Condition: heart failure
Age Group: adult
Sex: unknown
Population Size: 10495
Sources: Page: 6.1
Kidney dysfunction 1.8%
Disc. AE
49 mg 2 times / day multiple, oral
Recommended
Dose: 49 mg, 2 times / day
Route: oral
Route: multiple
Dose: 49 mg, 2 times / day
Co-administed with::
valsartan(51 mg/2/day)
Sources: Page: 6.1
unhealthy, adult
n = 10495
Health Status: unhealthy
Condition: heart failure
Age Group: adult
Sex: unknown
Population Size: 10495
Sources: Page: 6.1
Overview

Overview

Drug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
no
no
no
no
no
no
no
weak [IC50 40 uM]
weak
weak
weak
weak
weak
yes [IC50 126 uM]
yes [IC50 15 uM]
Drug as victim
PubMed

PubMed

TitleDatePubMed
Neprilysin Inhibition in Heart Failure with Reduced Ejection Fraction: A Clinical Review.
2015 Sep
Patents

Sample Use Guides

The recommended starting dose of ENTRESTO is 49/51 mg (sacubitril/valsartan) twice-daily. Double the dose of ENTRESTO after 2 to 4 weeks to the target maintenance dose of 97/103 mg (sacubitril/valsartan) twice-daily, as tolerated by the patient. (2.1)  Reduce the starting dose to 24/26 mg (sacubitril/valsartan) twice-daily for: - patients not currently taking an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin II receptor blocker (ARB) or previously taking a low dose of these agents (2.2) - patients with severe renal impairment (2.3) - patients with moderate hepatic impairment (2.4) Double the dose of ENTRESTO every 2 to 4 weeks to the target maintenance dose of 97/103 mg (sacubitril/valsartan) twice-daily, as tolerated by the patient. (2.2, 2.3, 2.4)
Route of Administration: Oral
Sacubitril at concentrations up to 50 uM had little or no effect on the accumulation of Rho123 or BDP in P-gp or BCRP overexpressing cells, respectively. The flux of [3H]digoxin, [3H]E3S, or CDFDA across C2BBe1, C2BBe1-MDR1/MRP2-KO, or C2BBe1-MDR1/BCRP-KO cell monolayers was not appreciably reduced in the presence of sacubitril (100 uM), respectively. Sacubitril weakly inhibited OAT1 transport activity (IC50 > 50 uM) and strongly inhibited OAT3 mediated transport.
Substance Class Chemical
Created
by admin
on Sat Jun 26 05:18:51 UTC 2021
Edited
by admin
on Sat Jun 26 05:18:51 UTC 2021
Record UNII
17ERJ0MKGI
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
SACUBITRIL
DASH   INN   JAN   USAN   WHO-DD  
INN   USAN  
Official Name English
AHU-377
Code English
SACUBITRIL [JAN]
Common Name English
SACUBITRIL COMPONENT OF ENTRESTO
Brand Name English
SACUBITRIL [MI]
Common Name English
ENTRESTO COMPONENT SACUBITRIL
Brand Name English
(2R,4S)-5-(BIPHENYL-4-YL)-4-((3-CARBOXYPROPIONYL)AMINO)-2-METHYLPENTANOIC ACID ETHYL ESTER
Systematic Name English
SACUBITRIL [USAN]
Common Name English
SACUBITRIL [INN]
Common Name English
SACUBITRIL [WHO-DD]
Common Name English
SACUBITRIL [ORANGE BOOK]
Common Name English
AHU377
Code English
Classification Tree Code System Code
NCI_THESAURUS C270
Created by admin on Sat Jun 26 05:18:51 UTC 2021 , Edited by admin on Sat Jun 26 05:18:51 UTC 2021
WHO-ATC C09DX04
Created by admin on Sat Jun 26 05:18:51 UTC 2021 , Edited by admin on Sat Jun 26 05:18:51 UTC 2021
Code System Code Type Description
EVMPD
SUB170848
Created by admin on Sat Jun 26 05:18:51 UTC 2021 , Edited by admin on Sat Jun 26 05:18:51 UTC 2021
PRIMARY
MERCK INDEX
M11856
Created by admin on Sat Jun 26 05:18:51 UTC 2021 , Edited by admin on Sat Jun 26 05:18:51 UTC 2021
PRIMARY
WIKIPEDIA
Sacubitril
Created by admin on Sat Jun 26 05:18:51 UTC 2021 , Edited by admin on Sat Jun 26 05:18:51 UTC 2021
PRIMARY
LACTMED
Sacubitril
Created by admin on Sat Jun 26 05:18:51 UTC 2021 , Edited by admin on Sat Jun 26 05:18:51 UTC 2021
PRIMARY
DRUG CENTRAL
5012
Created by admin on Sat Jun 26 05:18:51 UTC 2021 , Edited by admin on Sat Jun 26 05:18:51 UTC 2021
PRIMARY
NCI_THESAURUS
C152281
Created by admin on Sat Jun 26 05:18:51 UTC 2021 , Edited by admin on Sat Jun 26 05:18:51 UTC 2021
PRIMARY
CAS
149709-62-6
Created by admin on Sat Jun 26 05:18:51 UTC 2021 , Edited by admin on Sat Jun 26 05:18:51 UTC 2021
PRIMARY
RXCUI
1656328
Created by admin on Sat Jun 26 05:18:51 UTC 2021 , Edited by admin on Sat Jun 26 05:18:51 UTC 2021
PRIMARY RxNorm
EPA CompTox
149709-62-6
Created by admin on Sat Jun 26 05:18:51 UTC 2021 , Edited by admin on Sat Jun 26 05:18:51 UTC 2021
PRIMARY
FDA UNII
17ERJ0MKGI
Created by admin on Sat Jun 26 05:18:51 UTC 2021 , Edited by admin on Sat Jun 26 05:18:51 UTC 2021
PRIMARY
IUPHAR
7857
Created by admin on Sat Jun 26 05:18:51 UTC 2021 , Edited by admin on Sat Jun 26 05:18:51 UTC 2021
PRIMARY
DRUG BANK
DB09292
Created by admin on Sat Jun 26 05:18:51 UTC 2021 , Edited by admin on Sat Jun 26 05:18:51 UTC 2021
PRIMARY
INN
9819
Created by admin on Sat Jun 26 05:18:51 UTC 2021 , Edited by admin on Sat Jun 26 05:18:51 UTC 2021
PRIMARY
PUBCHEM
9811834
Created by admin on Sat Jun 26 05:18:51 UTC 2021 , Edited by admin on Sat Jun 26 05:18:51 UTC 2021
PRIMARY
ChEMBL
CHEMBL3137301
Created by admin on Sat Jun 26 05:18:51 UTC 2021 , Edited by admin on Sat Jun 26 05:18:51 UTC 2021
PRIMARY
Related Record Type Details
SALT/SOLVATE -> PARENT
METABOLIC ENZYME -> SUBSTRATE
BINDER->LIGAND
BINDING
SALT/SOLVATE -> PARENT
SALT/SOLVATE -> PARENT
Related Record Type Details
ACTIVE MOIETY
Name Property Type Amount Referenced Substance Defining Parameters References
ORAL BIOAVAILABILITY PHARMACOKINETIC
Volume of Distribution PHARMACOKINETIC
Tmax PHARMACOKINETIC ORAL ADMINISTRATION

Biological Half-life PHARMACOKINETIC