Details
| Stereochemistry | ABSOLUTE |
| Molecular Formula | C24H29N5O3 |
| Molecular Weight | 435.5188 |
| Optical Activity | UNSPECIFIED |
| Defined Stereocenters | 1 / 1 |
| E/Z Centers | 0 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
CCCCC(=O)N(CC1=CC=C(C=C1)C2=C(C=CC=C2)C3=NN=NN3)[C@H](C(C)C)C(O)=O
InChI
InChIKey=ACWBQPMHZXGDFX-JOCHJYFZSA-N
InChI=1S/C24H29N5O3/c1-4-5-10-21(30)29(22(16(2)3)24(31)32)15-17-11-13-18(14-12-17)19-8-6-7-9-20(19)23-25-27-28-26-23/h6-9,11-14,16,22H,4-5,10,15H2,1-3H3,(H,31,32)(H,25,26,27,28)/t22-/m1/s1
DescriptionSources: https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/entresto.pdfhttps://www.ncbi.nlm.nih.gov/pubmed/25052956http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021283s50lbl.pdfCurator's Comment: description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/mesh/2009869
Sources: https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/entresto.pdfhttps://www.ncbi.nlm.nih.gov/pubmed/25052956http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021283s50lbl.pdf
Curator's Comment: description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/mesh/2009869
Valsartan (DIOVAN®) is a tetrazole derivative, and specific angiotensin II type 1 (AT1) receptor blocker that is indicated for the treatment of hypertension, to lower blood pressure. Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme. Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Valsartan (DIOVAN®) blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis.
Originator
Approval Year
Targets
| Primary Target | Pharmacology | Condition | Potency |
|---|---|---|---|
Target ID: CHEMBL227 |
2.38 nM [Ki] | ||
Target ID: CHEMBL1944 |
2.3 nM [IC50] | ||
Target ID: CHEMBL227 |
2.43 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. ENTRESTO is usually administered in conjunction with other heart failure therapies, in place of an ACE inhibitor or other ARB. Launch Date2015 |
|||
| Primary | DIOVAN Approved UseDiovan is an angiotensin II receptor blocker (ARB) indicated for:
Treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions (1.1)
Treatment of heart failure (NYHA class II-IV); Diovan significantly reduced hospitalization for heart failure (1.2)
Reduction of cardiovascular mortality in clinically stable patients with left ventricular failure or left ventricular dysfunction following myocardial infarction (1.3) Launch Date2011 |
|||
| Primary | DIOVAN Approved UseDiovan is an angiotensin II receptor blocker (ARB) indicated for:
Treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions (1.1)
Treatment of heart failure (NYHA class II-IV); Diovan significantly reduced hospitalization for heart failure (1.2)
Reduction of cardiovascular mortality in clinically stable patients with left ventricular failure or left ventricular dysfunction following myocardial infarction (1.3) Launch Date2011 |
|||
| Palliative | DIOVAN Approved UseDiovan is an angiotensin II receptor blocker (ARB) indicated for:
Treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions (1.1)
Treatment of heart failure (NYHA class II-IV); Diovan significantly reduced hospitalization for heart failure (1.2)
Reduction of cardiovascular mortality in clinically stable patients with left ventricular failure or left ventricular dysfunction following myocardial infarction (1.3) Launch Date2011 |
Cmax
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
2808 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27128457 |
80 mg single, oral dose: 80 mg route of administration: Oral experiment type: SINGLE co-administered: |
VALSARTAN plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
5756 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27128457 |
80 mg single, oral dose: 80 mg route of administration: Oral experiment type: SINGLE co-administered: |
VALSARTAN plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
2.141 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21617777 |
160 mg single, oral dose: 160 mg route of administration: Oral experiment type: SINGLE co-administered: |
VALSARTAN plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN |
AUC
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
20650 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27128457 |
80 mg single, oral dose: 80 mg route of administration: Oral experiment type: SINGLE co-administered: |
VALSARTAN plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
34310 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27128457 |
80 mg single, oral dose: 80 mg route of administration: Oral experiment type: SINGLE co-administered: |
VALSARTAN plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
22.56 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21617777 |
160 mg single, oral dose: 160 mg route of administration: Oral experiment type: SINGLE co-administered: |
VALSARTAN plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN |
T1/2
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
8.45 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27128457 |
80 mg single, oral dose: 80 mg route of administration: Oral experiment type: SINGLE co-administered: |
VALSARTAN plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
8 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27128457 |
80 mg single, oral dose: 80 mg route of administration: Oral experiment type: SINGLE co-administered: |
VALSARTAN plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
9.55 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21617777 |
160 mg single, oral dose: 160 mg route of administration: Oral experiment type: SINGLE co-administered: |
VALSARTAN plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN |
Doses
| Dose | Population | Adverse events |
|---|---|---|
2.24 mg single, oral Overdose |
unknown, 25 years n = 1 Health Status: unknown Age Group: 25 years Sex: F Population Size: 1 Sources: |
Other AEs: Muscle cramps... |
640 mg 1 times / day steady, oral Highest studied dose Dose: 640 mg, 1 times / day Route: oral Route: steady Dose: 640 mg, 1 times / day Sources: |
unhealthy, 57.5 years n = 131 Health Status: unhealthy Age Group: 57.5 years Sex: M+F Population Size: 131 Sources: |
Disc. AE: Hyperkalemia... Other AEs: Dizziness, Headache... AEs leading to discontinuation/dose reduction: Hyperkalemia (1 patient) Other AEs:Dizziness (8.3%) Sources: Headache (9.2%) Back pain (5.8%) Upper respiratory tract infection (5.8%) Nasopharyngitis (5%) Diarrhea (5%) Hypoglycemia (5%) Peripheral edema (4.2%) Nausea (4.2%) |
320 mg 1 times / day steady, oral Recommended Dose: 320 mg, 1 times / day Route: oral Route: steady Dose: 320 mg, 1 times / day Sources: |
pregnant Health Status: pregnant Sources: |
Disc. AE: Disorder fetal... AEs leading to discontinuation/dose reduction: Disorder fetal Sources: |
320 mg 1 times / day steady, oral Recommended Dose: 320 mg, 1 times / day Route: oral Route: steady Dose: 320 mg, 1 times / day Sources: |
unhealthy n = 2316 Health Status: unhealthy Condition: hypertension Population Size: 2316 Sources: |
Disc. AE: Headache, Dizziness... AEs leading to discontinuation/dose reduction: Headache (2.3%) Sources: Dizziness (2.3%) |
320 mg 1 times / day steady, oral Recommended Dose: 320 mg, 1 times / day Route: oral Route: steady Dose: 320 mg, 1 times / day Sources: |
unhealthy n = 2506 Health Status: unhealthy Condition: Heart Failure Population Size: 2506 Sources: |
Disc. AE: Creatinine increased, Potassium increased... AEs leading to discontinuation/dose reduction: Creatinine increased (0.5%) Sources: Potassium increased (0.5%) |
AEs
| AE | Significance | Dose | Population |
|---|---|---|---|
| Muscle cramps | 1 patient | 2.24 mg single, oral Overdose |
unknown, 25 years n = 1 Health Status: unknown Age Group: 25 years Sex: F Population Size: 1 Sources: |
| Hyperkalemia | 1 patient Disc. AE |
640 mg 1 times / day steady, oral Highest studied dose Dose: 640 mg, 1 times / day Route: oral Route: steady Dose: 640 mg, 1 times / day Sources: |
unhealthy, 57.5 years n = 131 Health Status: unhealthy Age Group: 57.5 years Sex: M+F Population Size: 131 Sources: |
| Nausea | 4.2% | 640 mg 1 times / day steady, oral Highest studied dose Dose: 640 mg, 1 times / day Route: oral Route: steady Dose: 640 mg, 1 times / day Sources: |
unhealthy, 57.5 years n = 131 Health Status: unhealthy Age Group: 57.5 years Sex: M+F Population Size: 131 Sources: |
| Peripheral edema | 4.2% | 640 mg 1 times / day steady, oral Highest studied dose Dose: 640 mg, 1 times / day Route: oral Route: steady Dose: 640 mg, 1 times / day Sources: |
unhealthy, 57.5 years n = 131 Health Status: unhealthy Age Group: 57.5 years Sex: M+F Population Size: 131 Sources: |
| Diarrhea | 5% | 640 mg 1 times / day steady, oral Highest studied dose Dose: 640 mg, 1 times / day Route: oral Route: steady Dose: 640 mg, 1 times / day Sources: |
unhealthy, 57.5 years n = 131 Health Status: unhealthy Age Group: 57.5 years Sex: M+F Population Size: 131 Sources: |
| Hypoglycemia | 5% | 640 mg 1 times / day steady, oral Highest studied dose Dose: 640 mg, 1 times / day Route: oral Route: steady Dose: 640 mg, 1 times / day Sources: |
unhealthy, 57.5 years n = 131 Health Status: unhealthy Age Group: 57.5 years Sex: M+F Population Size: 131 Sources: |
| Nasopharyngitis | 5% | 640 mg 1 times / day steady, oral Highest studied dose Dose: 640 mg, 1 times / day Route: oral Route: steady Dose: 640 mg, 1 times / day Sources: |
unhealthy, 57.5 years n = 131 Health Status: unhealthy Age Group: 57.5 years Sex: M+F Population Size: 131 Sources: |
| Back pain | 5.8% | 640 mg 1 times / day steady, oral Highest studied dose Dose: 640 mg, 1 times / day Route: oral Route: steady Dose: 640 mg, 1 times / day Sources: |
unhealthy, 57.5 years n = 131 Health Status: unhealthy Age Group: 57.5 years Sex: M+F Population Size: 131 Sources: |
| Upper respiratory tract infection | 5.8% | 640 mg 1 times / day steady, oral Highest studied dose Dose: 640 mg, 1 times / day Route: oral Route: steady Dose: 640 mg, 1 times / day Sources: |
unhealthy, 57.5 years n = 131 Health Status: unhealthy Age Group: 57.5 years Sex: M+F Population Size: 131 Sources: |
| Dizziness | 8.3% | 640 mg 1 times / day steady, oral Highest studied dose Dose: 640 mg, 1 times / day Route: oral Route: steady Dose: 640 mg, 1 times / day Sources: |
unhealthy, 57.5 years n = 131 Health Status: unhealthy Age Group: 57.5 years Sex: M+F Population Size: 131 Sources: |
| Headache | 9.2% | 640 mg 1 times / day steady, oral Highest studied dose Dose: 640 mg, 1 times / day Route: oral Route: steady Dose: 640 mg, 1 times / day Sources: |
unhealthy, 57.5 years n = 131 Health Status: unhealthy Age Group: 57.5 years Sex: M+F Population Size: 131 Sources: |
| Disorder fetal | Disc. AE | 320 mg 1 times / day steady, oral Recommended Dose: 320 mg, 1 times / day Route: oral Route: steady Dose: 320 mg, 1 times / day Sources: |
pregnant Health Status: pregnant Sources: |
| Dizziness | 2.3% Disc. AE |
320 mg 1 times / day steady, oral Recommended Dose: 320 mg, 1 times / day Route: oral Route: steady Dose: 320 mg, 1 times / day Sources: |
unhealthy n = 2316 Health Status: unhealthy Condition: hypertension Population Size: 2316 Sources: |
| Headache | 2.3% Disc. AE |
320 mg 1 times / day steady, oral Recommended Dose: 320 mg, 1 times / day Route: oral Route: steady Dose: 320 mg, 1 times / day Sources: |
unhealthy n = 2316 Health Status: unhealthy Condition: hypertension Population Size: 2316 Sources: |
| Creatinine increased | 0.5% Disc. AE |
320 mg 1 times / day steady, oral Recommended Dose: 320 mg, 1 times / day Route: oral Route: steady Dose: 320 mg, 1 times / day Sources: |
unhealthy n = 2506 Health Status: unhealthy Condition: Heart Failure Population Size: 2506 Sources: |
| Potassium increased | 0.5% Disc. AE |
320 mg 1 times / day steady, oral Recommended Dose: 320 mg, 1 times / day Route: oral Route: steady Dose: 320 mg, 1 times / day Sources: |
unhealthy n = 2506 Health Status: unhealthy Condition: Heart Failure Population Size: 2506 Sources: |
PubMed
| Title | Date | PubMed |
|---|---|---|
| Pharmacological profile of valsartan: a potent, orally active, nonpeptide antagonist of the angiotensin II AT1-receptor subtype. | 1993 Oct |
|
| Angiotensin II receptor blockade with single doses of valsartan in healthy, normotensive subjects. | 1994 |
|
| Binding of valsartan to mammalian angiotensin AT1 receptors. | 1995 Nov 10 |
|
| Remodelling of resistance arteries in genetically hypertensive rats by treatment with valsartan, an angiotensin II receptor antagonist. | 1996 Jun-Jul |
|
| Development and validation of chiral high-performance liquid chromatographic methods for the quantitation of valsartan and of the tosylate of valinebenzyl ester. | 1996 Nov 8 |
|
| Valsartan, a new angiotensin II antagonist for the treatment of essential hypertension: a comparative study of the efficacy and safety against amlodipine. | 1996 Sep |
|
| Enantiomeric LC separation of valsartan on amylose based stationary phase. | 2009 Aug |
|
| Efficacy and safety of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, in Asian patients with hypertension: a randomized, double-blind, placebo-controlled study. | 2014 Apr |
|
| Determination of the R-enantiomer of valsartan in pharmaceutical formulation by capillary electrophoresis. | 2015 |
|
| LCZ696 : a new paradigm for the treatment of heart failure? | 2015 Feb |
|
| Sacubitril/valsartan (LCZ696) for the treatment of heart failure. | 2016 |
|
| Pharmacodynamic and Pharmacokinetic Profiles of Sacubitril/Valsartan (LCZ696) in Patients with Heart Failure and Reduced Ejection Fraction. | 2016 Aug |
Sample Use Guides
The recommended starting dose of ENTRESTO, previously known as LCZ696, 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.
Route of Administration:
Oral
In Vitro Use Guide
Sources: Von Lueder TG, Wang B, Kompa A, Huang L, Webb R, Jordan P, Krum H. ARNi, combined neprilysin and angiotensin receptor inhibition augments anti-fibrotic and anti-hypertrophic effects in vitro. Eur.Heart J. 2012;33:P5834.
Curator's Comment: ...
30 nM to 1 uM valsartan (LCZ696 component) in the presence of 10 uM LBQ657 (Sacubitril (LCZ696 component) metabolite) demonstrate anti-fibrotic and anti-hypertrophic effects on rat cardiac fibroblasts and cardiomyocytes, respectively, cultured with 100 nM angiotensin II
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5284633
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IDC67444MI
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SUBSTANCE RECORD
