Chemistry:Sacubitril

Short description: Chemical compound

Sacubitril

Clinical data
Other names	AHU-377
License data	EU EMA: by INN
ATC code	C09DX04 (WHO) (combination with valsartan)
Identifiers
IUPAC name 4-{[(2S,4R)-1-(4-Biphenylyl)-5-ethoxy-4-methyl-5-oxo-2-pentanyl]amino}-4-oxobutanoic acid
CAS Number	149709-62-6 Y
PubChem CID	9811834
DrugBank	DB09292
ChemSpider	7987587
UNII	17ERJ0MKGI
KEGG	D10225
Chemical and physical data
Formula	C24H29NO5
Molar mass	411.498 g·mol−1
3D model (JSmol)	Interactive image
SMILES CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCC(=O)O
InChI InChI=1S/C24H29NO5/c1-3-30-24(29)17(2)15-21(25-22(26)13-14-23(27)28)16-18-9-11-20(12-10-18)19-7-5-4-6-8-19/h4-12,17,21H,3,13-16H2,1-2H3,(H,25,26)(H,27,28)/t17-,21+/m1/s1 Key:PYNXFZCZUAOOQC-UTKZUKDTSA-N

Sacubitril (/səˈkjuːbɪtrɪl/; INN) is an antihypertensive drug used in combination with valsartan. The combination drug sacubitril/valsartan, known during trials as LCZ696 and marketed under the brand name Entresto, is a treatment for heart failure. 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, which is responsible for the edema seen sometimes in patients with the medication. This is why the medication is not recommended for patients with a history of pulmonary edema with the usage of ACE inhibitors.

Mechanism of action

Sacubitril is a prodrug that is activated to sacubitrilat (LBQ657) by de-ethylation via esterases. Sacubitrilat inhibits the enzyme neprilysin, which is responsible for the degradation of atrial and brain natriuretic peptide, two blood pressure–lowering peptides that work mainly by reducing blood volume. In addition, neprilysin degrades a variety of peptides including bradykinin, an inflammatory mediator.

Sacubitril activation to sacubitrilat

Synthesis

Industrial scale synthetic route to Secubitril

The large scale synthesis of Sacubritil begins with 4-bromo-1,1'-biphenyl, which is converted to its corresponding Grignard reagent; this is reacted directly with (S)-epichlorohydrin regioselectively at less-substituted site of the epoxide.

A Mitsunobu reaction with succinimide is performed, followed by acidic hydrolysis of the succinimide protecting group, 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 as the catalyst. This aldehyde undergoes a Wittig reaction to for the α.β-unsaturated ester, which is converted to the lithium carboxylate by hydrolysis using lithium hydroxide 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 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 in the presence of pyridine as a base.

See also

• Omapatrilat