(S)-5-[(ビフェニル-4-イル)メチル]ピロリジン-2-オン

Sacubitril is a neprilysin inhibitor prodrug developed by Novartis that was approved as part of an orally administered supramolecular sodium salt complex with the angiotensin receptor blocker (ARB) valsartan in the U.S. and EU in 2015. Sacubitril/valsartan (also known as LCZ-696) is a first-in-class dual angiotensin receptor blocker neprilysin inhibitor (ARNI) marketed for the treatment of chronic heart failure with reduced ejection fraction (HFrEF). It represents a novel mechanistic approach to targeting HFrEF and is the first pharmacologic agent approved for HFrEF since 2004. Sacubitril is metabolized by enzymatic conversion of the ethyl ester to the active diacid (LBQ-657, structure not disclosed), which inhibits neprilysin and prevents endogenous natriuretic peptide degradation. Neprilysin inhibitors like sacubitril are not effective as monotherapy and need to be combined with a reninangiotensin aldosterone system (RAAS) inhibitor such as valsartan. Notably, dual neprilysin and angiotensin-converting enzyme (ACE) inhibition, as in omapatrilat, was found to be associated with an increased risk of life-threatening angioedema due to increased bradykinin levels. In phase III clinical trials, sacubitril/ valsartan displayed a superior safety profile to enalapril, with a 20% decrease in heart failure hospitalizations or cardiovascular death and a 16% reduction in the risk of death from any cause. Sacubitril/valsartan is now recommended as the standard of care for HFrEF as an alternative to ACEs and ARBs.