MAK Scientific LLC, 151 South Bedford Street, Burlington, MA 01803 USA.
Center for Drug Discovery and Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA.
Bioorg Med Chem. 2019 Jan 1;27(1):55-64. doi: 10.1016/j.bmc.2018.11.003. Epub 2018 Nov 3.
Monoacylglycerol lipase (MGL) inhibition provides a potential treatment approach to glaucoma through the regulation of ocular 2-arachidonoylglycerol (2-AG) levels and the activation of CB1 receptors. Herein, we report the discovery of new series of carbamates as highly potent and selective MGL inhibitors. The new inhibitors showed potent nanomolar inhibitory activity against recombinant human and purified rat MGL, were selective (>1000-fold) against serine hydrolases FAAH and ABHD6 and lacked any affinity for the cannabinoid receptors CB1 and CB2. Protein-based H NMR experiments indicated that inhibitor 2 rapidly formed a covalent adduct with MGL with a residence time of about 6 h. This interconversion process "intrinsic reversibility" was exploited by modifications of the ligand's size (length and bulkiness) to generate analogs with "tunable' adduct residence time (τ). Inhibitor 2 was evaluated in a normotensive murine model for assessing intraocular pressure (IOP), which could lead to glaucoma, a major cause of blindness. Inhibitor 2 was found to decrease ocular pressure by ∼4.5 mmHg in a sustained manner for at least 12 h after a single ocular application, underscoring the potential for topically-administered MGL inhibitors as a novel therapeutic target for the treatment of glaucoma.
单酰甘油脂肪酶（MGL）抑制作用通过调节眼部 2-花生四烯酸甘油（2-AG）水平和激活 CB1 受体，为青光眼的治疗提供了一种潜在的方法。在此，我们报告了一系列新型氨基甲酸酯作为高度有效和选择性 MGL 抑制剂的发现。新抑制剂对重组人源和纯化大鼠 MGL 表现出有效的纳摩尔抑制活性，对丝氨酸水解酶 FAAH 和 ABHD6 具有选择性（>1000 倍），并且对大麻素受体 CB1 和 CB2 没有亲和力。基于蛋白质的 H NMR 实验表明，抑制剂 2 与 MGL 快速形成共价加合物，其停留时间约为 6 小时。这种互变过程“固有可逆性”通过修饰配体的大小（长度和体积）来利用，以产生具有“可调”加合物停留时间（τ）的类似物。在评估眼压（IOP）的正常眼压小鼠模型中评估了抑制剂 2，IOP 可能导致青光眼，这是失明的主要原因。发现抑制剂 2在单次眼部应用后至少 12 小时内以持续方式将眼压降低约 4.5mmHg，这突出了局部给予 MGL 抑制剂作为治疗青光眼的新治疗靶点的潜力。
