Research Division, Fuji Gotemba Research Laboratory, Chugai Pharmaceutical Co., Ltd, 1-135, Komakado, Gotemba, Shizuoka 412-8513, Japan.
Bioorg Med Chem. 2011 Sep 15;19(18):5334-41. doi: 10.1016/j.bmc.2011.08.005. Epub 2011 Aug 8.
5a-Carba-β-D-glucopyranose derivatives were synthesized and identified as novel SGLT2-selective inhibitors. These inhibitors exhibited potent SGLT2 inhibition with high selectivity over SGLT1. Among the tested compounds, 6f indicated the most potent hSGLT2 inhibition and the highest selectivity over hSGLT1. Moreover, the pharmacokinetics data also showed that 6h, which had the same aglycon structure as sergliflozin-active (3-active), had a threefold longer half-life time (T(1/2)) than sergliflozin (3) with a high distribution volume in db/db mice. Subsequently, 6h lowered blood glucose levels as much as 3 and showed longer hypoglycemic action than 3 in db/db mice.
5a-碳桥-β-D-吡喃葡萄糖衍生物被合成并鉴定为新型 SGLT2 选择性抑制剂。这些抑制剂对 SGLT2 具有很强的抑制作用，对 SGLT1 具有很高的选择性。在测试的化合物中，6f 对 hSGLT2 的抑制作用最强，对 hSGLT1 的选择性最高。此外，药代动力学数据还表明，具有与 sergliflozin-active（3-active）相同糖苷配基结构的 6h 在 db/db 小鼠中的半衰期（T(1/2)) 比 sergliflozin（3）长三倍，分布容积也更高。随后，6h 使 db/db 小鼠的血糖水平降低了约 3 个单位，并且其降血糖作用比 3 持续时间更长。
