Discovery of MK-8719, a Potent O‑GlcNAcase Inhibitor as a Potential Treatment for Tauopathies

Inhibition
of O-GlcNAcase (OGA) has emerged as a promising therapeutic
approach to treat tau pathology in neurodegenerative diseases such
as Alzheimer’s disease and progressive supranuclear palsy.
Beginning with carbohydrate-based lead molecules, we pursued an optimization
strategy of reducing polar surface area to align the desired drug-like
properties of potency, selectivity, high central nervous system (CNS)
exposure, metabolic stability, favorable pharmacokinetics, and robust
in vivo pharmacodynamic response. Herein, we describe the medicinal
chemistry and pharmacological studies that led to the identification
of (3aR,5S,6S,7R,7aR)-5-(difluoromethyl)-2-(ethylamino)-3a,6,7,7a-tetrahydro-5H-pyrano­[3,2-d]­thiazole-6,7-diol 42 (MK-8719), a highly potent and selective OGA inhibitor
with excellent CNS penetration that has been advanced to first-in-human
phase I clinical trials.