In vitro: LCZ696 is a single molecule that is comprised of molecular moieties of valsartan, an ARB, and AHU377, a neprilysin inhibitor (1:1 ratio). AHU377 is converted by enzymatic cleavage of the ethyl ester into the active neprilysin inhibiting metabolite LBQ657. The inactive NEPi precursor, AHU377, does not inhibit collagen accumulation in fibroblasts nor cardiac myocyte hypertrophy. In cardiac fibroblasts, the active NEPi LBQ657 had no discernible effects. In contrast, LBQ657 modestly inhibits cardiac myocyte hypertrophy.
In vivo: In humans, AHU377 (tmax 0.5-1.1 h) are absorbed quickly. AHU377 is converted rapidly into LBQ657 with its tmax being reached in 1.9-3.5 h. Mean t1/2 values for the biologically active LBQ657 is 9.9-11.1 h. In vehicle-treated dogs, ANF increases urinary sodium excretion from 17.3±3.6 to 199.5±18.4 μequiv/kg/min. This effect is potentiated significantly in animals which receive AHU377. Urinary volume is also potentiated in animals which receive an iv administration of AHU377.
| Molecular Weight | 430.52 |
| Formula | C24H28Ca0.5NO5 |
| CAS Number | 1369773-39-6 |
| Solubility (25°C) | 54 mg/mL in DMSO |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
| Related Neprilysin (NEP) Products |
|---|
| Opiorphin
Opiorphin is an opioid peptide that simultaneously inhibits the activity of two enkephalinolytic enzymes, human neutral exopeptide endogenous peptidase hNEP (EC 3.4.24.11) and human exoamino peptidase hAP-N (EC 3.4.11.2). |
| Thiorphan
Thiorphan was a selective neprilysin inhibitor with an IC50 value of 6.9 nM. Increased bradykinin-induced relaxation of isolated porcine coronary rings with potassium chloride precontraction under hypoxic but very oxygen conditions. |
| Sacubitril
Sacubitril (AHU-377) is a potent NEP inhibitor with an IC50 of 5 nM. Sacubitril (AHU-377) is a component of the heart failure medicine LCZ696. |
| LBQ657
LBQ657 is an active metabolite of Sacubitril and an inhibitor of enkephalinase (NEP). |
| Omapatrilat
Omapatrilat is a vasopeptidase inhibitor, a dual metalloprotease inhibitor of neutral endopeptidase (NEP, neprilysin) and angiotensin converting enzyme (ACE). |
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