Sacubitril (;

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway. Before the advent of motorized transportation, they also provided accomm ...

) is an

antihypertensive Antihypertensives are a class of drugs that are used to treat hypertension (high blood pressure). Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke, heart failure, kidney failure and myocardial infa ...

drug used in combination with

valsartan Valsartan, sold under the brand name Diovan among others, is a medication used to treat high blood pressure, heart failure, and diabetic kidney disease. It belongs to a class of medications referred to as angiotensin II receptor blockers (AR ...

. The combination drug sacubitril/valsartan, known during trials as ''LCZ696'' and marketed under the brand name ''Entresto'', is a treatment for

heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to Cardiac cycle, fill with and pump blood. Although symptoms vary based on which side of the heart is affected, HF ...

. It was approved under the FDA's priority review process for use in heart failure on July 7, 2015.

Side effects

Sacubitril increases levels of

bradykinin Bradykinin (BK) (from Greek ''brady-'' 'slow' + ''-kinin'', ''kīn(eîn)'' 'to move') is a peptide that promotes inflammation. It causes arterioles to dilate (enlarge) via the release of prostacyclin, nitric oxide, and endothelium-derived hyperpo ...

, which is responsible for the

edema Edema (American English), also spelled oedema (British English), and also known as fluid retention, swelling, dropsy and hydropsy, is the build-up of fluid in the body's tissue (biology), tissue. Most commonly, the legs or arms are affected. S ...

seen sometimes in patients with the medication. This is why the medication is not recommended for patients with a history of

pulmonary edema Pulmonary edema (British English: oedema), also known as pulmonary congestion, is excessive fluid accumulation in the tissue or air spaces (usually alveoli) of the lungs. This leads to impaired gas exchange, most often leading to shortness ...

with the usage of

ACE inhibitor Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a class of medication used primarily for the treatment of high blood pressure and heart failure. This class of medicine works by causing relaxation of blood vessels as well as a decr ...

Mechanism of action

Sacubitril is a

prodrug A prodrug is a pharmacologically inactive medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be ...

that is activated to

sacubitrilat Sacubitrilat (INN; or LBQ657) is the active metabolite of the antihypertensive drug sacubitril, which is used in the treatment of heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an im ...

(LBQ657) by de- ethylation via

esterase In biochemistry, an esterase is a class of enzyme that splits esters into an acid and an alcohol in a chemical reaction with water called hydrolysis (and as such, it is a type of hydrolase). A wide range of different esterases exist that differ ...

s. Sacubitrilat inhibits the enzyme

neprilysin Neprilysin (; also known as membrane metallo-endopeptidase (MME), neutral endopeptidase (NEP), cluster of differentiation 10 (CD10) and common acute lymphoblastic leukemia antigen (CALLA)) is an enzyme that in humans is encoded by the ''MME'' ge ...

, which is responsible for the degradation of

atrial The atrium (; : atria) is one of the two upper chambers in the heart that receives blood from the circulatory system. The blood in the atria is pumped into the heart ventricles through the atrioventricular mitral and tricuspid heart valves. ...

and brain natriuretic peptide, two blood pressure–lowering

peptide Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...

s that work mainly by reducing blood volume. In addition, neprilysin degrades a variety of peptides including

, an inflammatory mediator. Sacubitril activation

Synthesis

The large scale synthesis of sacubritil begins with 4-bromo-1,1'-biphenyl, which is converted to its corresponding

Grignard reagent Grignard reagents or Grignard compounds are chemical compounds with the general formula , where X is a halogen and R is an organic group, normally an alkyl or aryl. Two typical examples are methylmagnesium chloride and phenylmagnesium bromi ...

; this is reacted directly with (''S'')-epichlorohydrin regioselectively at less-substituted site of the epoxide. A

Mitsunobu reaction The Mitsunobu reaction is an organic reaction that converts an alcohol into a variety of functional groups, such as an ester, using triphenylphosphine and an azodicarboxylate such as diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxy ...

with

succinimide Succinimide is an organic compound with the formula (CH2)2(CO)2NH. This white solid is used in a variety of organic syntheses, as well as in some industrial silver plating processes. The compound is classified as a cyclic imide. It may be prepared ...

is performed, followed by acidic hydrolysis of the succinimide

protecting group A protecting group or protective group is introduced into a molecule by chemical modification of a functional group to obtain chemoselectivity in a subsequent chemical reaction. It plays an important role in multistep organic synthesis. In man ...

, hydrolysis of the alkyl chloride using sodium hydroxide and protection of the free amine with a ''tert''-butoxycarbonyl (Boc) group. The primary alcohol is oxidized using bleach with

TEMPO In musical terminology, tempo (Italian for 'time'; plural 'tempos', or from the Italian plural), measured in beats per minute, is the speed or pace of a given musical composition, composition, and is often also an indication of the composition ...

as the catalyst. This aldehyde undergoes a

Wittig reaction The Wittig reaction or Wittig olefination is a chemical reaction of an aldehyde or ketone with a triphenyl phosphonium ylide called a Wittig reagent. Wittig reactions are most commonly used to convert aldehydes and ketones to alkenes. Most o ...

to for the α.β-unsaturated ester, which is converted to the lithium carboxylate by hydrolysis using

lithium hydroxide Lithium hydroxide is an inorganic compound with the formula LiOH. It can exist as anhydrous or hydrated, and both forms are white hygroscopic solids. They are soluble in water and slightly soluble in ethanol. Both are available commercially. While ...

in aqueous ethanol. Asymmetric hydrogenation using a ruthenium catalyst and a chiral bisphosphine ligand sets the second stereocenter. The carboxylate is esterified by reaction with

thionyl chloride Thionyl chloride is an inorganic compound with the chemical formula . It is a moderately Volatility (chemistry), volatile, colourless liquid with an unpleasant acrid odour. Thionyl chloride is primarily used as a Halogenation, chlorinating reagen ...

to form the acyl chloride, which is reacted with ethanol. The acidic conditions under which the acyl chloride is generated result in removal of the Boc group, which allows for direct reaction of the amine with

succinic anhydride Succinic anhydride, is an organic compound with the molecular formula (CH2CO)2O. This colorless solid is the acid anhydride of succinic acid. Preparation In the laboratory, this material can be prepared by dehydration of succinic acid. Such dehy ...

in the presence of

pyridine Pyridine is a basic (chemistry), basic heterocyclic compound, heterocyclic organic compound with the chemical formula . It is structurally related to benzene, with one methine group replaced by a nitrogen atom . It is a highly flammable, weak ...

as a base. :

References

{{Reflist, refs= {{cite journal , vauthors = McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR , display-authors = 6 , title = Angiotensin-neprilysin inhibition versus enalapril in heart failure , journal = The New England Journal of Medicine , volume = 371 , issue = 11 , pages = 993–1004 , date = September 2014 , pmid = 25176015 , doi = 10.1056/NEJMoa1409077 , hdl-access = free , hdl = 2336/552372 {{cite journal , vauthors = Gu J, Noe A, Chandra P, Al-Fayoumi S, Ligueros-Saylan M, Sarangapani R, Maahs S, Ksander G, Rigel DF, Jeng AY, Lin TH, Zheng W, Dole WP , display-authors = 6 , title = Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi) , journal = Journal of Clinical Pharmacology , volume = 50 , issue = 4 , pages = 401–414 , date = April 2010 , pmid = 19934029 , doi = 10.1177/0091270009343932 , s2cid = 24853279 {{Cite book , vauthors = Schubert-Zsilavecz M, Wurglics M , title=Neue Arzneimittel 2010/2011 , language=de {{cite web, url=http://spo.escardio.org/eSlides/view.aspx?eevtid=46&fp=13 , archive-url = https://web.archive.org/web/20140912012635/http://spo.escardio.org/eSlides/view.aspx?eevtid=46&fp=13 , archive-date = 12 September 2014 , title=HFpEF in the Future: New Diagnostic Techniques and Treatments in the Pipeline, vauthors = Solomon SD , location=Boston , page=48 , access-date=2012-01-26 Antihypertensive agents Biphenyls Carboxylate esters Ethyl esters Prodrugs Butyramides Carboxylic acids

Side effects

Mechanism of action

Synthesis

See also

References