Details
Stereochemistry | ABSOLUTE |
Molecular Formula | 2C24H28NO5.Ca |
Molecular Weight | 861.044 |
Optical Activity | UNSPECIFIED |
Defined Stereocenters | 4 / 4 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
[Ca++].CCOC(=O)[C@H](C)C[C@@H](CC1=CC=C(C=C1)C2=CC=CC=C2)NC(=O)CCC([O-])=O.CCOC(=O)[C@H](C)C[C@@H](CC3=CC=C(C=C3)C4=CC=CC=C4)NC(=O)CCC([O-])=O
InChI
InChIKey=DDLCKLBRBPYKQS-OXXXZDCLSA-L
InChI=1S/2C24H29NO5.Ca/c2*1-3-30-24(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;/h2*4-12,17,21H,3,13-16H2,1-2H3,(H,25,26)(H,27,28);/q;;+2/p-2/t2*17-,21+;/m11./s1
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.
Originator
Sources: http://adisinsight.springer.com/drugs/800035182
Curator's Comment: # Novartis
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL1944 |
5.0 nM [IC50] | ||
Target ID: CHEMBL1944 |
5.0 nM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | ENTRESTO Approved UseENTRESTO 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 Date2015 |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
16345 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26990595/ |
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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26990595/ |
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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26990595/ |
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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26990595/ |
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
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
147111 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26990595/ |
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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26990595/ |
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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26990595/ |
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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26990595/ |
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
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
18.4 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26990595/ |
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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26990595/ |
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
Dose | Population | Adverse 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... |
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... |
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... |
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... |
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%) Sources: Page: 6.1Hypotension (1.7%) Hyperkalemia (1.3%) |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
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
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
OverviewOther
Other Inhibitor | Other Substrate | Other Inducer |
---|---|---|
Drug as perpetrator
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207620Orig1s000ClinPharmR.pdf#page=13 Page: 13.0 |
no | |||
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207620Orig1s000ClinPharmR.pdf#page=36 Page: 36.0 |
yes |
PubMed
Title | Date | PubMed |
---|---|---|
Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi). | 2010 Apr |
|
Angiotensin-neprilysin inhibition versus enalapril in heart failure. | 2014 Sep 11 |
|
The Role of Neprilysin Inhibitors in Cardiovascular Disease. | 2015 Dec |
|
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
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/28281384
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.
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ACTIVE MOIETY
SUBSTANCE RECORD