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Details

Stereochemistry ABSOLUTE
Molecular Formula C22H25NO5
Molecular Weight 383.4376
Optical Activity UNSPECIFIED
Defined Stereocenters 2 / 2
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of SACUBITRILAT

SMILES

C[C@H](C[C@@H](CC1=CC=C(C=C1)C2=CC=CC=C2)NC(=O)CCC(O)=O)C(O)=O

InChI

InChIKey=DOBNVUFHFMVMDB-BEFAXECRSA-N
InChI=1S/C22H25NO5/c1-15(22(27)28)13-19(23-20(24)11-12-21(25)26)14-16-7-9-18(10-8-16)17-5-3-2-4-6-17/h2-10,15,19H,11-14H2,1H3,(H,23,24)(H,25,26)(H,27,28)/t15-,19+/m1/s1

HIDE SMILES / InChI

Molecular Formula C22H25NO5
Molecular Weight 383.4376
Charge 0
Count
MOL RATIO 1 MOL RATIO (average)
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 2 / 2
E/Z Centers 0
Optical Activity UNSPECIFIED

Description

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

Originator

Approval Year

Targets

Primary TargetPharmacologyConditionPotency
5.0 nM [IC50]
5.0 nM [IC50]

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
ENTRESTO

Cmax

ValueDoseCo-administeredAnalytePopulation
16345 ng/mL
200 mg 2 times / day steady-state, oral
SACUBITRILAT plasma
Homo sapiens
9103 ng/mL
100 mg 2 times / day steady-state, oral
SACUBITRILAT plasma
Homo sapiens
2408 ng/mL
200 mg 2 times / day steady-state, oral
SACUBITRIL plasma
Homo sapiens
1229 ng/mL
100 mg 2 times / day steady-state, oral
SACUBITRIL plasma
Homo sapiens

AUC

ValueDoseCo-administeredAnalytePopulation
147111 ng × h/mL
200 mg 2 times / day steady-state, oral
SACUBITRILAT plasma
Homo sapiens
82633 ng × h/mL
100 mg 2 times / day steady-state, oral
SACUBITRILAT plasma
Homo sapiens
3153 ng × h/mL
200 mg 2 times / day steady-state, oral
SACUBITRIL plasma
Homo sapiens
1537 ng × h/mL
100 mg 2 times / day steady-state, oral
SACUBITRIL plasma
Homo sapiens

T1/2

ValueDoseCo-administeredAnalytePopulation
18.4 h
200 mg 2 times / day steady-state, oral
SACUBITRILAT plasma
Homo sapiens
3.9 h
200 mg 2 times / day steady-state, oral
SACUBITRIL plasma
Homo sapiens

Doses

AEs

Drug as perpetrator​

Drug as victim

PubMed

Sample Use Guides

In Vivo Use Guide
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
In Vitro Use Guide
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
Record UNII
SPI5PBF81S
Record Status Validated (UNII)
Record Version