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AHU-377

AHU-377 structure

CAS No:
149709-62-6
Formula:
C24H29NO5
Chemical Name:
AHU-377
Synonyms:
4-(((2R,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-Methyl-5-oxopentan-2-yl)aMino)-4-oxobutanoic acid;AHU-377;4-(((2S,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-Methyl-5-oxopentan-2-yl)aMino)-4-oxobutanoic acid;(2R,4S)-5-(Biphenyl-4-yl)-4-[(3-carboxypropionyl)amino]-2-methylpentanoic acid ethyl ester;AHU-377,149709-62-6;AHU-37;AHU377; AHU 377; SACUBITRIL;LCZ696(valsartan + sacubitril) impurity 4
Categories:
Biochemical Engineering > Inhibitors

Description

AHU377 and angiotensin IIAT1 receptor antagonist valsartan at a molar ratio of 1: 1 compose LCZ696. LCZ696 was a dual inhibitor of angiotensin II (AT2) receptor and enkephalinase (Neprilysin) receptor. And with its better antihypertensive efficacy than standard antihypertensive drugs, it is a new drug for the treatment of heart failure. AHU377 is a prodrug that converts the active form of the enzyme cleavage LBQ657 ethyl ester. So far its efficacy and safety in milestone phase III surpas.

Sacubitril is a member of biphenyls.|Sacubitril is a prodrug neprilysin inhibitor used in combination with valsartan to reduce the risk of cardiovascular events in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction. It was approved by the FDA after being given the status of priority review for 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.|Sacubitril is a neprilysn (NEP) inhibitor prodrug with natriuretic activity. Upon administration, sacubitril is metabolized by esterases to its active metabolite, sacubitrilat, which inhibits NEP, a neutral endopeptidase that cleaves natriuretic peptides such as atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and c-type natriuretic peptide (CNP), as well as certain vasoconstricting peptides including as angiotensin I and II, and endothelin-1. Additionally, sacubitrilat may inhibit NEP-mediated catabolism of certain peptide-based agents, thereby improving their in vivo stability and increasing tumor cell exposure.

ChEBI: Sacubitril is a member of biphenyls.

AHU-377 Basic Attributes

Molecular Weight：

411.49

Exact Mass：

411.49

EC Number：

1592732-453-0

UNII：

17ERJ0MKGI

DSSTox ID：

DTXSID20164370

NCI Thesaurus Code：

C152281

Color/Form：

colorless

ATC Code：

C09DX04

Characteristics

PSA：

92.7

XLogP3：

3.96

Density：

1.151±0.06 g/cm3(Predicted)

Boiling Point：

656.9±55.0 °C(Predicted)

Flash Point：

351.1±31.5 °C

Refractive Index：

1.549

PKA：

4.72±0.10(Predicted)

Critical Temperature & Pressure：

Sealed in dry,Store in freezer, under -20°C

Toxicity

Toxicity Summary：

The most common adverse reactions (≥5%) are hypotension, hyperkalemia, cough, dizziness, and renal failure.

Protein Binding：

Sacubitril and it's metabolite, LBQ657 are highly bound to plasma protein (94-97%).

Drug Information

Drug Indication：

Used in combination with valsartan to reduce the risk of cardiovascular events in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction. It is usually administered in conjunction with other heart failure therapies, in place of an ACE inhibitor or other ARB.|FDA Label|Entresto is indicated in adult patients for treatment of symptomatic chronic heart failure with reduced ejection fraction.|Neparvis is indicated in adult patients for treatment of symptomatic chronic heart failure with reduced ejection fraction.|Treatment of heart failure|Prevention of heart failure

Pharmacology：

n a 7-day valsartan-controlled study in patients with reduced ejection fraction (HFrEF), administration of sacubitril + valsartan (Entresto) resulted in a significant non-sustained increase in natriuresis, increased urine cGMP, and decreased plasma MR-proANP and NT-proBNP compared to valsartan. In a 21-day study in HFrEF patients, it significantly increased urine ANP and cGMP and plasma cGMP, and decreased plasma NT-proBNP, aldosterone and endothelin-1. In clinical studies, this combination had no effect on QTc interval.

Absorption：

Peak plasma concentrations of sacubitril and it's metabolite, LBQ657 are reached in 0.5 hours and 2 hours respectively. Food does not clinically affect the systemic exposure of sacubitril or LBQ657. The oral bioavailability of sacubitril is >60%. It should be noted that the valsartan found in this combination is more bioavailable than other market available valsartan.|52% to 68% of sacubitril (primarily as the active metabolite LBQ657) is excreted in urine. 37% to 48% of sacubitril (primarily as LBQ657) is excreted in feces|103 L

Metabolism/Metabolites：

Sacubitril is metabolized to LBQ657 by esterases. A low concentration (<10%) of a hydroxyl metabolite has been identified in plasma.

Biological Half-Life：

The half life of sacubitril is 1.1 to 3.6 hours, and the half life of it's metabolite LBQ657 is 9.9 to 11.1 hours.

Mechanism of Action：

Sacubitril's active metabolite, LBQ657 inhibits neprilysin, a neutral endopeptidase that would typically cleave natiuretic peptides, which includes: 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. Therefore, the inhibition of neprilysin leads to reduced breakdown and increased concentration of endogenous natriuretic peptides in addition to increased levels of vasoconstricting hormones such as angiotensin II. (However, when combined with valsartan, would result in blocking of angiotensin II to its receptor, preventing the vasoconstrictive effects and resulting in a decrease in vascular resistance and blood pressure.) Cardiovascular and renal effects of sacubitril is a result of the increased levels of peptides that are normally degraded by neprilysin.

MeSH Entry Terms：

(2R,4S)-5-(biphenyl-4-yl)-4-((3-carboxypropionyl)amino)-2-methylpentanoic acid ethyl ester

AHU-377 Use and Manufacturing

Uses

Sacubitril is an antihypertensive drug used in combination with valsartan. The combination drug, valsartan/sacubitril, known during trials as LCZ696 and marketed under the brand name, Entresto, is a treatment for heart failure.

Use Classification：

Human drugs -> Entresto -> EMA Drug Category|Angiotensin II antagonists, other combinations, Agents acting on the renin-angiotensin system -> Human pharmacotherapeutic group|Human drugs -> Neparvis -> EMA Drug Category|Agents acting on the renin-angiotensin system -> Human pharmacotherapeutic group|Human Drugs -> EU pediatric investigation plans|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients

Computed Properties

Molecular Weight:411.5
XLogP3:3.7
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:12
Exact Mass:411.20457303
Monoisotopic Mass:411.20457303
Topological Polar Surface Area:92.7
Heavy Atom Count:30
Complexity:550
Defined Atom Stereocenter Count:2
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes

Drug Function and Efficacy

Through its active metabolite LBQ657, it inhibits enkephalinase (neutral endopeptidase; NEP), increasing the levels of peptides degraded by enkephalinase (e.g., natriuretic peptides).

This ingredient has been used in drugs with the following functions (note: it does not mean that the ingredient itself has the following health functions)

Related Drugs

Sacubitril/Valsartan Sodium Tablets
Ingredients	Active ingredient of this product: Sacubitril-valsartan sodium Chemical name: Octadecasodium hexa(4-{[(1S,3R)-1-([1,1'-biphenyl)-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate)hexa(N-pentanoyl-N-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-L-valine)-water (1/15) Chemical structure: Molecular formula: C24H28NNaO5•C24H27N5N2O3•21/2H20 Molecular weight: 957.99
Indication	Contraindications: ACEI: Entresto is contraindicated with ACEI because the concurrent use of ACEIs while inhibiting neprilysin (NEP) may increase the risk of angioedema. Entresto must be started 36 hours after the last dose of ACEI. Entresto must be started 36 hours after the last dose of ACEI (see [Contraindications] and [Dosage and Administration]). Aliskiren: Entresto is contraindicated with aliskiren in patients with type 2 diabetes (see [Contraindications]). Renal impairment (eGFR
Specifications	100mg*14 tablets

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