LCZ 696
[CAS 936623-90-4]

Identification

• Classification: Biochemical >> Inhibitor >> Endocrinology & hormones >> RAAS inhibitor
• Name: LCZ 696
• Molecular Formula: 2(C₂₄H₂₉N₅O₃).2(C₂₄H₂₉NO₅).5(H₂O).₆Na
• Molecular Weight: 1922.03
• CAS Registry Number: 936623-90-4
• EC Number: 810-144-3

Safety Data

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Skin sensitization	Skin Sens.	1B	H317
Reproductive toxicity	Repr.	2	H361d
Eye irritation	Eye Irrit.	2	H319

Discovery and Applications

LCZ696 is the former development code name for sacubitril/valsartan, a fixed-dose combination drug used in the treatment of chronic heart failure with reduced ejection fraction (HFrEF).

It is a first-in-class angiotensin receptor–neprilysin inhibitor (ARNI) that combines two pharmacologically distinct agents:

* Sacubitril: a prodrug that is converted in vivo to LBQ657, a neprilysin inhibitor
* Valsartan: an angiotensin II type 1 (AT1) receptor blocker (ARB)

Structurally, LCZ696 is not a single covalent molecule but a co-crystal complex (salt complex) formed between the anionic form of valsartan and the sacubitril-derived cationic component in a defined 1:1 molar ratio. This formulation improves stability and enables simultaneous delivery of both active pharmacophores.

Sacubitril contains a prodrug ester functionality that is hydrolyzed after absorption to release the active neprilysin inhibitor LBQ657. Neprilysin is a neutral endopeptidase responsible for degradation of several vasoactive peptides, including natriuretic peptides, bradykinin, and adrenomedullin. Inhibition of neprilysin increases levels of these peptides, promoting vasodilation, natriuresis, and diuresis.

Valsartan, on the other hand, selectively blocks the AT1 receptor, preventing angiotensin II from exerting its effects such as vasoconstriction, aldosterone secretion, sodium retention, and sympathetic activation. This leads to reduced blood pressure and decreased cardiac workload.

The combination in LCZ696 is pharmacologically synergistic because neprilysin inhibition alone can increase angiotensin II levels (since angiotensin II is also a neprilysin substrate). The presence of valsartan prevents these potentially adverse effects by blocking AT1 receptors, while allowing beneficial natriuretic peptide signaling to predominate.

From a physicochemical standpoint, LCZ696 exists as a crystalline complex that enhances oral bioavailability and controls pharmacokinetic behavior of both components. The system is designed to maintain balanced exposure of sacubitril-derived and valsartan-derived species after administration.

Clinically, LCZ696 (sacubitril/valsartan) was shown in large outcome trials to reduce cardiovascular mortality and heart failure hospitalization compared with enalapril, an ACE inhibitor. This led to its approval and widespread use in guideline-directed medical therapy for HFrEF.

Mechanistically, its benefit arises from dual modulation of two opposing neurohormonal systems: enhancement of natriuretic peptide pathways via neprilysin inhibition and suppression of renin–angiotensin–aldosterone system (RAAS) signaling via AT1 blockade.

Overall, LCZ696 is a fixed-dose combination therapeutic system composed of sacubitril (a neprilysin inhibitor prodrug) and valsartan (an angiotensin receptor blocker), designed to achieve complementary neurohormonal modulation in heart failure management.