Sacubitril

Chemical Identity

Property	Value
Chemical Formula	C24H29NO5
Molecular Weight	415.5 Da
CAS Number	149709-62-6
Peptide Class	Neprilysin Inhibitor Prodrug
Route	Oral (with valsartan as sacubitril/valsartan)

Structure

Sacubitril (AHU-377) is a prodrug that is hydrolyzed by esterases to the active metabolite LBQ657, a neprilysin inhibitor. It is formulated as a sodium salt complex with valsartan (Entresto), creating the first-in-class angiotensin receptor-neprilysin inhibitor (ARNI).

Mechanism of Action

LBQ657 inhibits neprilysin (neutral endopeptidase), the enzyme that degrades natriuretic peptides (ANP, BNP, CNP), bradykinin, and other vasoactive peptides. This increases levels of endogenous natriuretic peptides, promoting vasodilation, natriuresis, diuresis, and suppression of RAAS and sympathetic activity. Combined with valsartan’s ARB action.

Clinical Applications

• Heart failure with reduced ejection fraction: First-line (Entresto)
• Chronic HF: Mortality benefit over enalapril (PARADIGM-HF)
• Hypertension: Blood pressure reduction (off-label)
• HFpEF: Under investigation (PARAGON-HF)

Pharmacokinetics

• Half-life: 1.5 hours (sacubitril), 12 hours (LBQ657)
• Tmax: 0.5 hours (sacubitril), 2 hours (LBQ657)
• Bioavailability: >60%
• Metabolism: Esterase-mediated hydrolysis
• Elimination: Renal (52-68%)
• Route: Oral (twice daily)

Safety and Side Effects

Hypotension (18%), hyperkalemia (12%), renal impairment, cough (10%), angioedema (rare, contraindicated with ACE inhibitors), and dizziness. Requires 36-hour washout when switching from ACE inhibitors.

References

• McMurray, J.J., et al. (2014). PARADIGM-HF: sacubitril/valsartan for heart failure. New England Journal of Medicine, 371, 993-1004.
• Solomon, S.D., et al. (2019). PARAGON-HF: sacubitril/valsartan for HFpEF. New England Journal of Medicine, 381, 1609-1620.