Verubecestat (TFA)

Verubecestat (MK-8931) TFA is an orally active, high-affinity BACE1 and BACE2 inhibitor with K_i values of 2.2 nM and 0.38 nM. Verubecestat TFA effectively reduces Aβ40 and has the potential for Alzheimer's Disease^[1][2]. IC50 & Target:Ki: 2.2 nM (BACE1) and 0.38 nM (BACE2)^[1] In Vitro:Verubecestat TFA (MK-8931) is a β-site amyloid precursor protein cleaving enzyme 1/2 (BACE1/2) inhibitor. Verubecestat TFA does not significantly inhibit human CYP isoforms 1A2, 2C9, 2C19, 2D6, and 3A4 (all IC₅₀>40 μM), indicating that the compound is unlikely to be a perpetrator of CYP-mediated drug-drug interactions^[1].
Verubecestat TFA has IC₅₀s of 2.1 nM, 0.7 nM, 4.4 nM for Aβ1-40, Aβ1-42, sAPPβ in HEK293 APP^Swe/Lon cells^[1].
In Vivo:Verubecestat TFA (MK-8931; 3 mg/kg; IV or oral) has a T_1/2 of 1.9 hours, a CL of 46 mL/min/kg, a V_ss of 5.4 L/kg, a C _max of 0.27 μM and a AUC of 1.1 μM•h for Sprague-Dawley (SD) rats^[1].
Verubecestat TFA (1 mg/kg; IV) has a T_1/2 of 4.9 hours, a CL of 21 mL/min/kg, a V_ss of 7.5 L/kg for cynomolgus monkeys^[1].
Verubecestat TFA (1 mg/kg; IV) has a T_1/2 of 9.7 hours, a CL of 4.3 mL/min/kg, a V_ss of 2.7 L/kg for beagle dogs^[1].
Verubecestat TFA (30 mg/kg; orally; BID for 5 days) causes a modest (1.4-fold) induction of CYP 3A1 activity but does not significantly alter the expression of CYPs 1A1, 1A2, 2B, 3A2, or 4A in rats^[1].
Verubecestat TFA dose-dependently reduces CSF and cortex Aβ40 with ED₅₀ values of 5 and 8 mg/kg, respectively, corresponding to unbound plasma EC₅₀ values of 48 and 81 nM, respectively^[1].
Verubecestat TFA (3 and 10 mg/kg; orally) reduces profound, sustained of CSF Aβ40 levels and has peak effects on CSF Aβ lowering (72 and 81% reduction at 3 and 10 mg/kg, respectively) 12 h after dosing^[1].