Monoacylglycerol lipase (MAGL) inhibition provides a potential treatment approach to neuroinflammation through modulation of both the endocannabinoid pathway and arachidonoyl signaling in the central nervous system (CNS). Herein we report the discovery of compound 15 (PF-06795071), a potent and selective covalent MAGL inhibitor, featuring a novel trifluoromethyl glycol leaving group that confers significant physicochemical property improvements as compared with earlier inhibitor series with more lipophilic leaving groups. The design strategy focused on identifying an optimized leaving group that delivers MAGL potency, serine hydrolase selectivity, and CNS exposure while simultaneously reducing log D, improving solubility, and minimizing chemical lability. Compound 15 achieves excellent CNS exposure, extended 2-AG elevation effect in vivo, and decreased brain inflammatory markers in response to an inflammatory challenge.

中文翻译：

---

发现三氟甲基乙二醇氨基甲酸酯作为有效的和选择性的共价单酰基甘油脂肪酶（MAGL）抑制剂，可用于治疗神经炎症

单酰基甘油脂肪酶（MAGL）抑制通过调节中枢神经系统（CNS）中的内源性大麻素途径和花生四烯酰信号提供了一种潜在的神经炎症治疗方法。在本文中，我们报告发现了一种化合物15（PF-06795071），这是一种有效的选择性共价MAGL抑制剂，其特征在于新型三氟甲基乙二醇离去基团，与较早的具有更多亲脂性离去基团的抑制剂系列相比，具有显着的理化性质改善。该设计策略着重于确定优化的离去基团，该离去基团可提供MAGL效力，丝氨酸水解酶选择性和CNS暴露，同时降低log  D，提高溶解度并最大程度地降低化学稳定性。化合物15 可实现出色的中枢神经系统暴露，在体内可延长2-AG的升高作用，并可响应炎症挑战降低脑部炎症标志物。