Verubecestat (MK-8931) TFA is an orally active, high-affinity BACE1 and BACE2 inhibitor with Ki values of 2.2 nM and 0.38 nM, which effectively reduces Aβ40 and has the potential for Alzheimer's Disease[1].[2].
体内研究
Pharmacokinetic studies in Sprague-Dawley rats reveal that, whether administered intravenously or orally at 3 mg/kg, Verubecestat TFA has a half-life (T1/2) of 1.9 hours, a clearance (CL) rate of 46 mL/min/kg, a steady-state volume of distribution (Vss) of 5.4 L/kg, a maximum concentration (Cmax) of 0.27 μM, and an area under the curve (AUC) of 1.1 μM•h[1].
Further pharmacokinetic profiling in cynomolgus monkeys and beagle dogs, with an IV dose of 1 mg/kg, shows a T1/2 of 4.9 hours and 9.7 hours, CL rates of 21 mL/min/kg and 4.3 mL/min/kg, and Vss values of 7.5 L/kg and 2.7 L/kg, respectively[1].
In rats, a 30 mg/kg oral dose administered twice daily for five days leads to a modest 1.4-fold induction in CYP 3A1 activity without significantly affecting the expression of other CYP isoforms[1].
Dose-dependent reductions in cerebrospinal fluid (CSF) and cortex Aβ40 are observed, with ED50 values of 5 and 8 mg/kg, respectively, translating to unbound plasma EC50 values of 48 and 81 nM, respectively[1].
Oral administration of 3 and 10 mg/kg doses results in profound, sustained reductions in CSF Aβ40 levels, achieving peak effects (72% and 81% reduction, respectively) 12 hours post-dosing[1].
体外研究
Verubecestat TFA shows no significant inhibition of human CYP isomers 1A2, 2C9, 2C19, 2D6, and 3A4 (IC50 >40 μM), suggesting that the compound is unlikely to be a major contributor to CYP-mediated drug-drug interactions [1].
In HEK293 APPSwe/Lon cells, Verubecestat TFA displays IC50 values of 2.1 nM for Aβ1-40, 0.7 nM for Aβ1-42, and 4.4 nM for sAPPβ, highlighting its efficacy in reducing key Alzheimer’s disease biomarkers[1].
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