MK-8719

MK-8719 is an inhibitor of O-GlcNAcase (OGA; K_i = 7.9 nM for the human enzyme).¹ It is selective for OGA over β-hexosaminidase (K_i = >10,000 nM for the human enzyme). MK-8719 increases the levels of O-GlcNAcylated proteins in rat PC12 adrenal medulla cells (EC₅₀ = 52.7 nM). It increases brain levels of O-GlcNAcylated proteins in rats when administered at a dose of 10 mg/kg. Dietary administration of MK-8719 reduces the levels of aggregated tau proteins in the brain, the levels of neurofibril tangles in the entorhinal cortex, and spontaneous locomotor activity, as well as increases cortex, hippocampal, and lateral ventricular volume and forebrain weight, in an rTg4510 transgenic mouse model of Alzheimer's disease.²

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1. Selnick, H.G., Hess, J.F., Tang, C., et al. Discovery of MK-8719, a potent O-GlcNAcase inhibitor as a potential treatment for tauopathies. J. Med. Chem. 62(22), 10062-10097 (2019).

2. Wang, X., Li, W., Marcus, J., et al. MK-8719, a novel and selective O-GlcNAcase inhibitor that reduces the formation of pathological tau and ameliorates neurodegeneration in a mouse model of tauopathy. J. Pharmacol. Exp. Ther. 374(2), 252-263 (2020).