MK-8719 is a selective and potent small molecule inhibitor of the O-GlcNAcase (OGA) enzyme with ki of 7.9nM for hOGA.
In vitro, MK-8719 is a potent inhibitor of the human OGA enzyme with comparable activity against the corresponding enzymes from mouse, rat, and dog.[2]
In vivo, oral administration of MK-8719 elevates brain and peripheral blood mononuclear cell O-GlcNAc levels in a dose-dependent manner. In addition, positron emission tomography imaging studies demonstrate robust target engagement of MK-8719 in the brains of rats and rTg4510 mice. In the rTg4510 mouse model of human tauopathy, MK-8719 significantly increases brain O-GlcNAc levels and reduces pathologic tau. The reduction in tau pathology in rTg4510 mice is accompanied by attenuation of brain atrophy, including reduction of forebrain volume loss as revealed by volumetric magnetic resonance imaging analysis.[2]
[1] Harold G Selnick, et al. J Med Chem. 2019 Nov 27;62(22):10062-10097. [2] Xiaohai Wang, et al. J Pharmacol Exp Ther. 2020 Aug;374(2):252-263.