SACUBITRILAT

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 Search

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

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207620Orig1s000lbl.pdf | https://www.drugbank.ca/drugs/DB09292

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 Target	Pharmacology	Condition	Potency
Neprilysin 29 Target ID: CHEMBL1944 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207620Orig1s000lbl.pdf	Inhibitor 8297		5.0 nM [IC50]
Neprilysin 29 Target ID: CHEMBL1944 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27302413 \| https://www.ncbi.nlm.nih.gov/pubmed/7752193/	Inhibitor 8297		5.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Chronic heart failure 21 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207620Orig1s000lbl.pdf http://reference.medscape.com/drug/entresto-sacubitril-valsartan-1000010 https://www.entrestohcp.com/mechanism-of-action	Primary		Approved 8429	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 2015

C_max

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	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	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	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	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	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	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	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	VALSARTAN	SACUBITRIL plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

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	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	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: https://pubmed.ncbi.nlm.nih.gov/27230850/	healthy, 18-65 years n = 22 Health Status: healthy Age Group: 18-65 years Sex: M+F Population Size: 22 Sources: https://pubmed.ncbi.nlm.nih.gov/27230850/	Other AEs: Orthostatic hypotension... Other AEs: Orthostatic hypotension (13.64%) Sources: https://pubmed.ncbi.nlm.nih.gov/27230850/
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: https://pubmed.ncbi.nlm.nih.gov/27230850/	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: https://pubmed.ncbi.nlm.nih.gov/27230850/	Other AEs: Orthostatic hypotension... Other AEs: Orthostatic hypotension (50%) Sources: https://pubmed.ncbi.nlm.nih.gov/27230850/
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: https://pubmed.ncbi.nlm.nih.gov/27230850/	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: https://pubmed.ncbi.nlm.nih.gov/27230850/	Other AEs: Orthostatic hypotension... Other AEs: Orthostatic hypotension (25%) Sources: https://pubmed.ncbi.nlm.nih.gov/27230850/
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: https://pubmed.ncbi.nlm.nih.gov/27230850/	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: https://pubmed.ncbi.nlm.nih.gov/27230850/	Other AEs: Orthostatic hypotension... Other AEs: Orthostatic hypotension (62.5%) Sources: https://pubmed.ncbi.nlm.nih.gov/27230850/
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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207620Orig1s000lbl.pdf Page: 6.1	unhealthy, adult n = 10495 Health Status: unhealthy Condition: heart failure Age Group: adult Sex: unknown Population Size: 10495 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207620Orig1s000lbl.pdf 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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207620Orig1s000lbl.pdf Page: 6.1

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: https://pubmed.ncbi.nlm.nih.gov/27230850/	healthy, 18-65 years n = 22 Health Status: healthy Age Group: 18-65 years Sex: M+F Population Size: 22 Sources: https://pubmed.ncbi.nlm.nih.gov/27230850/
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: https://pubmed.ncbi.nlm.nih.gov/27230850/	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: https://pubmed.ncbi.nlm.nih.gov/27230850/
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: https://pubmed.ncbi.nlm.nih.gov/27230850/	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: https://pubmed.ncbi.nlm.nih.gov/27230850/
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: https://pubmed.ncbi.nlm.nih.gov/27230850/	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: https://pubmed.ncbi.nlm.nih.gov/27230850/
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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207620Orig1s000lbl.pdf Page: 6.1	unhealthy, adult n = 10495 Health Status: unhealthy Condition: heart failure Age Group: adult Sex: unknown Population Size: 10495 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207620Orig1s000lbl.pdf 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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207620Orig1s000lbl.pdf Page: 6.1	unhealthy, adult n = 10495 Health Status: unhealthy Condition: heart failure Age Group: adult Sex: unknown Population Size: 10495 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207620Orig1s000lbl.pdf 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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207620Orig1s000lbl.pdf Page: 6.1	unhealthy, adult n = 10495 Health Status: unhealthy Condition: heart failure Age Group: adult Sex: unknown Population Size: 10495 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207620Orig1s000lbl.pdf Page: 6.1

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 781	inhibitor 1767 inducer 389	inhibitor 1852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1524 CYP2C8 911 CYP2E1 882 CYP3A4/5 278 OAT3 642 OATP1B1 788 MATE1 306 OCT1 512 OCT2 647	CYP 270 OAT3 339	CYP1A2 701 CYP2B6 547

Drug as perpetrator

Target	Modality	Activity
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207620Orig1s000ClinPharmR.pdf#page=36 Page: 36.0	no
CYP2C8 965	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207620Orig1s000ClinPharmR.pdf#page=36 Page: 36.0	no
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207620Orig1s000ClinPharmR.pdf#page=36 Page: 36.0	no
CYP2E1 970	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207620Orig1s000ClinPharmR.pdf#page=36 Page: 36.0	no
CYP3A4/5 335	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207620Orig1s000ClinPharmR.pdf#page=36 Page: 36.0	no
OCT1 543	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207620Orig1s000ClinPharmR.pdf#page=36 Page: 36.0	no
OCT2 648	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207620Orig1s000ClinPharmR.pdf#page=36 Page: 36.0	no
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207620Orig1s000ClinPharmR.pdf#page=36 Page: 36.0	weak [IC50 40 uM]
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207620Orig1s000ClinPharmR.pdf#page=36 Page: 36.0	weak
CYP2B6 1001	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207620Orig1s000ClinPharmR.pdf#page=36 Page: 36.0	weak
CYP2C9 1819	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207620Orig1s000ClinPharmR.pdf#page=36 Page: 36.0	weak
CYP3A4 1925	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207620Orig1s000ClinPharmR.pdf#page=36 Page: 36.0	weak
MATE1 308	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207620Orig1s000ClinPharmR.pdf#page=36 Page: 36.0	weak
OATP1B1 803	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207620Orig1s000ClinPharmR.pdf#page=36 Page: 36.0	yes [IC50 126 uM]
OAT3 644	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207620Orig1s000ClinPharmR.pdf#page=36 Page: 36.0	yes [IC50 15 uM]

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
CYP 270	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207620Orig1s000ClinPharmR.pdf#page=13 Page: 13.0	no
OAT3 339	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207620Orig1s000ClinPharmR.pdf#page=36 Page: 36.0	yes

Sourcing

Vendor/Aggregator	ID	URL
AA Blocks	AA001LVR	https://www.aablocks.com/goods/Goods/detail?id=AA001LVR
AEchem Scientific Corp., USA	AE049184	http://www.aechemsc.com/info_products/AE049184.php
Aaron Chemicals	AR001MNJ	http://www.aaronchem.com/149709-44-4
Alichem	19117924	http://www.alichem.com/en/products/149709-44-4.html
BLD Pharm	BD571663	http://www.bldpharm.com/products/149709-44-4.html
CSNpharm	CSN21977	https://www.csnpharm.com/products/sacubitrilat.html
Chem Scene	CS-6593	http://www.chemscene.com/149709-44-4.html
Chemspace	CSSB00020642239	https://chem-space.com/CSSB00020642239
DC Chemicals	DC31376	http://www.dcchemicals.com//product_show-LBQ-657.html
MedChem Express	HY-17620	https://www.medchemexpress.com/Sacubitrilat.html
Selleck Chemicals	S3388	http://www.selleckchem.com/products/sacubitrilat.html
Sigma-Aldrich	SML2064_SIGMA	https://www.sigmaaldrich.com/catalog/product/sigma/sml2064?utm_source=pubchem&utm_campaign=pubchem_2017&utm_medium=referral
Smolecule	S542281	http://www.smolecule.com/products/s542281
THE BioTek	bt-281154	https://www.thebiotek.com/product/inhibitors/bt-281154
eNovation Chemicals	D673507	https://www.enovationchem.com/ProductDetails.asp?ProductID=D673507
eNovation Chemicals	D763014	https://www.enovationchem.com/ProductDetails.asp?ProductID=D763014

PubMed

Title	Date	PubMed

Patents

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.

Name

Type

Language

SACUBITRILAT

Official Name

English

(2R,4S)-5-(BIPHENYL-4-YL)-4-((3-CARBOXYPROPIONYL)AMINO)-2-METHYLPENTANOIC ACID

Systematic Name

English

LBQ657

Code

English

SACUBITRILAT [MI]

Common Name

English

sacubitrilat [INN]

Common Name

English

Sacubitrilat [WHO-DD]

Common Name

English

LBQ-657

Code

English

Classification Tree Code System Code

NDF-RT

N0000191728