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| Other names | AHU-377 |
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| Formula | C24H29NO5 |
| Molar mass | 411.498 g·mol−1 |
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Sacubitril (/səˈkjuːbɪtrɪl/;INN) is anantihypertensive drug used in combination withvalsartan. The combination drugsacubitril/valsartan, known during trials asLCZ696 and marketed under the brand nameEntresto, is a treatment forheart failure.[1] It was approved under the FDA'spriority review process for use in heart failure on July 7, 2015.
Sacubitril increases levels ofbradykinin, which is responsible for theedema seen sometimes in patients with the medication. This is why the medication is not recommended for patients with a history ofpulmonary edema with the usage ofACE inhibitors.[citation needed]
Sacubitril is aprodrug that is activated tosacubitrilat (LBQ657) by de-ethylation viaesterases.[2] Sacubitrilat inhibits the enzymeneprilysin,[3] which is responsible for the degradation ofatrial andbrain natriuretic peptide, two blood pressure–loweringpeptides that work mainly by reducing blood volume.[4] In addition, neprilysin degrades a variety of peptides includingbradykinin,[5] an inflammatory mediator.
The large scale synthesis of sacubritil begins with 4-bromo-1,1'-biphenyl, which is converted to its correspondingGrignard reagent; this is reacted directly with (S)-epichlorohydrin regioselectively at less-substituted site of the epoxide.[6][7]
AMitsunobu reaction withsuccinimide is performed, followed by acidic hydrolysis of the succinimideprotecting group, hydrolysis of the alkyl chloride using sodium hydroxide and protection of the free amine with atert-butoxycarbonyl (Boc) group. The primary alcohol is oxidized using bleach withTEMPO as the catalyst. This aldehyde undergoes aWittig reaction to for the α.β-unsaturated ester, which is converted to the lithium carboxylate by hydrolysis usinglithium 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 withthionyl 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 withsuccinic anhydride in the presence ofpyridine as a base.
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