Banyu Tsukuba Research Institute, Banyu Pharmaceutical Co. Ltd, Japan.
Bioorg Med Chem Lett. 2010 Mar 1;20(5):1619-22. doi: 10.1016/j.bmcl.2010.01.041. Epub 2010 Jan 20.
Glucokinase activators (GKAs) are currently under investigation as potential antidiabetic agents by many pharmaceutical companies. Most of GKAs reported previously possess N-aminothiazol-2-yl amide moiety in their structures because the aminothiazole moiety interacts with glucokinase (GK) and shows strong GK activation. During the development of N-aminothiazol-2-yl amide derivatives, we identified a bioactivation and metabolic liability of 2-aminothizole substructure of GKA 3 by assessing covalent binding, metabolites in liver microsomes and glutathione (GSH) trap assay.
葡萄糖激酶激活剂 (GKAs) 目前正受到许多制药公司的关注，被视为潜在的抗糖尿病药物。以前报道的大多数 GKAs 在其结构中都具有 N-氨噻唑-2-基酰胺部分，因为氨基噻唑部分与葡萄糖激酶 (GK) 相互作用并表现出强烈的 GK 激活作用。在 N-氨噻唑-2-基酰胺衍生物的开发过程中，我们通过评估共价结合、肝微粒体中的代谢物和谷胱甘肽 (GSH) 捕获试验，发现了 GKA 3 的 2-氨基噻唑亚结构的生物活化和代谢缺陷。
