Research Division, Fuji Gotemba Research Laboratory, Chugai Pharmaceutical Co. Ltd, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
Bioorg Med Chem. 2012 Jul 1;20(13):4117-27. doi: 10.1016/j.bmc.2012.04.053. Epub 2012 May 4.
C-Aryl 5a-carba-β-d-glucopyranose derivatives were synthesized and evaluated for inhibition activity against hSGLT1 and hSGLT2. Modifications to the substituents on the two benzene rings resulted in enhanced hSGLT2 inhibition activity and extremely high hSGLT2 selectivity versus SGLT1. Using the created superimposed model, the reason for the high hSGLT2 selectivity was speculated to be that additional substituents occupied a new space, in a different way than known inhibitors. Among the tested compounds, the ethoxy compound 5h with high hSGLT2 selectivity exhibited more potent and longer hypoglycemic action in db/db mice than our O-carbasugar compound (1) and sergliflozin (2), which could be explained by its improved PK profiles relative to those of the two compounds. These results indicated that 5h might be a promising drug candidate for the treatment of type 2 diabetes.
C-芳基 5a-碳杂-β-D-吡喃葡萄糖苷衍生物被合成并评估了对 hSGLT1 和 hSGLT2 的抑制活性。对两个苯环上取代基的修饰导致对 hSGLT2 的抑制活性增强，并且对 SGLT1 的选择性极高。使用创建的叠加模型，推测高 hSGLT2 选择性的原因是额外的取代基以不同于已知抑制剂的方式占据了一个新的空间。在所测试的化合物中，具有高 hSGLT2 选择性的乙氧基化合物 5h 在 db/db 小鼠中表现出比我们的 O-碳杂糖化合物 (1) 和 sergliflozin (2) 更强和更持久的降血糖作用，这可以通过其相对于两种化合物的改善的 PK 谱来解释。这些结果表明，5h 可能是治疗 2 型糖尿病的有前途的候选药物。
