Verubecestat

A potent, selective, structurally unique BACE1 inhibitor with Ki of 2.2 nM; displays high selectivity for BACE1 over other key aspartyl proteases, notably cathepsin D; reduces plasma, cerebrospinal fluid (CSF), and brain concentrations of Aβ40, Aβ42, and sAPPβ; well tolerated and produces reductions in Aβ40, Aβ42, and sAPPβ in the CSF of both healthy human subjects and AD patients in clinical evaluation.Alzheimer's Disease Phase 3 Clinical (In Vitro) :Verubecestat (MK-8931) is a β-site amyloid precursor protein cleaving enzyme 1/2 (BACE1/2) inhibitor. Verubecestat 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.Verubecestat has IC50s of 2.1 nM, 0.7 nM, 4.4 nM for Aβ1-40, Aβ1-42, sAPPβ in HEK293 APPSwe/Lon cells. (In Vivo) :Verubecestat (MK-8931; 3 mg/kg; IV or oral) has a T1/2 of 1.9 hours, a CL of 46 mL/min/kg, a Vss 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.Verubecestat (1 mg/kg; IV) has a T1/2 of 4.9 hours, a CL of 21 mL/min/kg, a Vss of 7.5 L/kg for cynomolgus monkeys.Verubecestat (1 mg/kg; IV) has a T1/2 of 9.7 hours, a CL of 4.3 mL/min/kg, a Vss of 2.7 L/kg for beagle dogs.Verubecestat (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.Verubecestat 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.Verubecestat (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.