Ki: 2.2 and 3.4 nM for human and mouse Bace1, respectively

Verubecestat (MK-8931) is a BACE1 inhibitor.

β-Amyloid (Aβ) peptides are regarded to be involved in the etiology of AD. BACE1 is required for the Aβ production, and BACE1 inhibition is therefore an promising target for the AD treatment.

In vitro: Verubecestat has been identified as a potent inhibitor of both human and mouse Bace1 and verubecestat could also inhibit the production of Ab40, Ab42, and sAPPb in human cells with similar potency. Verubecestat was also found to be a potent inhibitor of purified human BACE2. Moreover, verubecestat was essentially inactive with over 45,000-fold selectivity in the purified human aspartyl proteases cathepsin D, cathepsin E, and pepsin and had a very weak inhibitor of purified human renin with 15,000-fold selectivity. In addition, verubecestat was also found to have minimal or no activity against various tested receptors, ion channels, transporters, as well as enzymes [1].

In vivo: Verubecestat could reduce plasma, cerebrospinal fluid, and brain concentrations of Aβ40, Aβ42, and sAPPβ after acute and chronic administration to both rats and monkeys. Moreover, the chronic treatment of rats and monkeys with verubecestat at exposures >40-fold higher than those tested in clinical trials did not cause many of the adverse effects previously reported to BACE inhibition. In rabbits and mice but not in monkeys, fur hypopigmentation was found [1].

Clinical trial: Single and multiple doses of verubecestat were generally well tolerated and produced reductions in Aβ40, Aβ42, and sAPPβ in the CSF [1].

Reference:[1] Kennedy ME et al.  The BACE1 inhibitor verubecestat (MK-8931) reduces CNS β-amyloid in animal models and in Alzheimer"s disease patients. Sci Transl Med.2016 Nov 2;8(363):363ra150.