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.