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.

O-连接β-N-乙酰葡糖胺糖苷酶（O-GlcNAcase, OGA）的抑制作用，已成为治疗阿尔茨海默病（Alzheimer’s disease）、进行性核上性麻痹等神经退行性疾病中tau蛋白病理的极具前景的治疗策略。本研究从基于碳水化合物的先导分子出发，采用降低极性表面积的优化策略，以兼顾效力、选择性、高中枢神经系统（central nervous system, CNS）暴露量、代谢稳定性、良好药代动力学特性以及显著的体内药效学响应等理想的类药物性质。本文详述了通过药物化学与药理学研究，最终成功鉴定得到(3aR,5S,6S,7R,7aR)-5-(二氟甲基)-2-(乙氨基)-3a,6,7,7a-四氢-5H-吡喃并[3,2-d]噻唑-6,7-二醇42（MK-8719）的全过程；该化合物是一种高活性、高选择性的OGA抑制剂，具备优异的中枢神经系统穿透性，目前已推进至首次人体I期临床试验阶段。