Sacubitril | Encyclopeptide

Chemical Identity

Property	Value
Chemical Formula	C24H29NO5
Molecular Weight	415.49 g/mol
CAS Number	149709-62-6
IUPAC Name	4-{[(2S,4R)-1-(4-biphenylsulfonyl)-4-(2,2-dimethylpropanoyloxy)pyrrolidin-2-yl]methoxy}-4-oxobutanoic acid
Peptide Class	Neprilysin Inhibitor (Prodrug)
Sequence Homology	Non-peptide small molecule

Structure

Sacubitril is a prodrug that is metabolized by esterases to the active metabolite LBQ657 (sacubitrilat). While not a peptide itself, sacubitril’s mechanism centers on inhibiting neprilysin (NEP), a zinc metallopeptidase that degrades natriuretic peptides (ANP, BNP, CNP), bradykinin, and other vasoactive peptides. The drug is administered as a molecular complex with valsartan (sacubitril/valsartan, LCZ696) in a 1:1 molar ratio.

Mechanism of Action

LBQ657 inhibits neprilysin (neutral endopeptidase, NEP), preventing the degradation of vasoactive peptides:

ANP/BNP: Enhanced natriuretic, diuretic, and vasodilatory effects
Bradykinin: Potentiated vasodilation and anti-fibrotic effects
Adrenomedullin: Enhanced vasodilation and cardioprotection
Substance P: Modestly increased levels

Combined with AT1 receptor blockade (valsartan), this dual approach addresses both neurohormonal excess and maladaptive signaling in heart failure.

Clinical Applications

Sacubitril/valsartan (Entresto) is approved for:

Heart failure with reduced ejection fraction (HFrEF): First-line therapy replacing ACE inhibitors
Heart failure with preserved ejection fraction (HFpEF): Approved based on PARAGON-HF trial

In the PARADIGM-HF trial, sacubitril/valsartan reduced cardiovascular death by 20% and heart failure hospitalization by 21% compared to enalapril.

Pharmacokinetics

Half-life: Sacubitril 1.4 hours; LBQ657 11.5 hours
Tmax: Sacubitril 0.5 hours; LBQ657 2 hours
Bioavailability: >60% (oral)
Metabolism: Sacubitril hydrolyzed by esterases to LBQ657
Elimination: Renal (52-68% as LBQ657)

Safety and Side Effects

Hypotension (18%), hyperkalemia (12%), cough (9%), dizziness (6%), and renal impairment. Angioedema risk is lower than with ACE inhibitors but patients with prior angioedema on ACE inhibitors should not receive sacubitril/valsartan. A 36-hour washout period is required when switching from an ACE inhibitor to avoid bradykinin-mediated angioedema. Contraindicated with concomitant aliskiren use in diabetic patients.

References

McMurray, J.J., et al. (2014). Angiotensin-neprilysin inhibition versus enalapril in heart failure. New England Journal of Medicine, 371, 993-1004.
Solomon, S.D., et al. (2019). Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction. New England Journal of Medicine, 381, 1609-1620.