Research, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Takeda California, Inc., 9625 Towne Centre Drive, San Diego, California 92121, United States.
J Med Chem. 2021 Jan 28;64(2):1103-1115. doi: 10.1021/acs.jmedchem.0c01712. Epub 2021 Jan 6.
-GlcNAcase (OGA) has received increasing attention as an attractive therapeutic target for tau-mediated neurodegenerative disorders; however, its role in these pathologies remains unclear. Therefore, potent chemical tools with favorable pharmacokinetic profiles are desirable to characterize this enzyme. Herein, we report the discovery of a potent and novel OGA inhibitor, compound , comprising an aminopyrimidine scaffold, identified by virtual screening based on multiple methodologies combining structure-based and ligand-based approaches, followed by sequential optimization with a focus on ligand lipophilicity efficiency. This compound was observed to increase the level of -GlcNAcylated protein in cells and display suitable pharmacokinetic properties and brain permeability. Crystallographic analysis revealed that the chemical series bind to OGA via characteristic hydrophobic interactions, which resulted in a high affinity for OGA with moderate lipophilicity. Compound could serve as a useful chemical probe to help establish a proof-of-concept of OGA inhibition as a therapeutic target for the treatment of tauopathies.
-GlcNAcase（OGA）作为一种有吸引力的治疗tau 介导的神经退行性疾病的靶点，受到越来越多的关注；然而，其在这些病理中的作用仍不清楚。因此，需要具有良好药代动力学特性的有效化学工具来表征这种酶。本文报道了一种有效的新型 OGA 抑制剂的发现，该抑制剂由基于虚拟筛选的包含氨基嘧啶骨架的化合物 组成，筛选方法基于多种结构和基于配体的方法相结合，随后重点进行了配体脂溶性效率的连续优化。该化合物被观察到能够增加细胞内 -GlcNAc 化蛋白的水平，并表现出合适的药代动力学特性和脑渗透性。晶体结构分析表明，该化学系列通过特征性的疏水相互作用与 OGA 结合，从而对 OGA 具有高亲和力和中等脂溶性。化合物 可用作有用的化学探针，有助于建立 OGA 抑制作为治疗 tau 病的治疗靶点的概念验证。
