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
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
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 |
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
Cmax
AUC
Doses
AEs
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
OverviewOther
Other Inhibitor | Other Substrate | Other Inducer |
---|---|---|
Drug as perpetrator
Drug as victim
Sourcing
PubMed
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.