tcsc2119 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.

IC50 & Target: IC50: 5 nM (NEP)^[1]

In Vitro: Sacubitril (AHU-377) is a single molecule that is comprised of molecular moieties of valsartan, an ARB, and Sacubitril (AHU-377), a neprilysin inhibitor (1:1 ratio). Sacubitril (AHU-377) is converted by enzymatic cleavage of the ethyl ester into the active neprilysin inhibiting metabolite LBQ657^[2]. The inactive NEPi precursor, Sacubitril (AHU-377), 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^[3].

In Vivo: In humans, Sacubitril (AHU-377) (t_max 0.5-1.1 h) are absorbed quickly. Sacubitril (AHU-377) is converted rapidly into LBQ657 with its t_max being reached in 1.9-3.5 h. Mean t_1/2 values for the biologically active LBQ657 is 9.9-11.1 h^[2]. In vehicle-treated dogs, ANF increases urinary sodium excretion from 17.3±3.6 to 199.5±18.4 pequivkglmin. This effect is potentiated significantly in animals which receive Sacubitril (AHU-377). Urinary volume is also potentiated in animals which receive an iv administration of Sacubitril (AHU-377)^[1].