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基本信息
半水卡格列嗪
坎格列嗪半水物
卡格列净半水物
卡格列净半水合物
坎格列净(半水)
坎格列嗪半水合物
坎格列净半水合物
坎格列净半水化合物
卡格列净半水化合物
TA7284 hemihydrate
TA-7284 hemihydrate
Invokana hemihydrate
Canagliflozin hydrate
Cagliflozin heMihydrate
JNJ28431754 hemihydrate
JNJ 28431754 hemihydrate
JNJ-28431754 hemihydrate
Canagliflozin heMihydrate
物理化学性质
常见问题列表
以T-1095为基础,许多药厂都在围绕T-1095衍生物开发SGLT-2抑制剂糖尿病药物。日本三菱的化学家,围绕C-葡萄糖苷及N-葡萄糖苷展开了研究,目标就是要开发出针对SGLT-2抑制剂的药物。
研究结果初步显示,联苯结构的C-葡萄糖苷的化合物抑制活性较弱;相反,苄基苯胺的N-葡萄糖苷的化合物展现出强的体外抑制活性,但是N-葡萄糖苷的代谢稳定性相对还是较差。因此,后续合成了一系列芳环C-葡萄糖苷和硫唑嘌呤芳香N-葡萄糖苷化合物,并比较了相关化合物的活性及尿排糖量,结果如下:
通过上述数据可以看出,IC50显示,化合物20及化合物21的活性表现出较为明显的优势;UGE方面,化合物21比化合物20高出近50%。噻吩衍生物在一系列C-葡萄糖苷化合物中体现出最高的效能;对于R1的取代,卤素和短链烷烃较氢原子展现出更高的体外活性;体内效能和化学稳定性方面,R2的取代基团为芳基要优于烷基或者卤素基团。因此,最终选择化合物21为目标化合物进一步进行研究,也就是未来的坎格列净 Canagliflozin(TA-7284)。
Target | Value |
mSGLT2
(Cell-free assay) | 2 nM |
hSGLT2
(Cell-free assay) | 4.4 nM |
Canagliflozin inhibits Na + -dependent 14 C-AMG uptake in CHO-hSGLT2 cells, with an IC 50 of 4.4±1.2 nM. Similar IC 50 values are obtained in CHO-rSGLT2 and CHO-mSGLT2 cells (IC 50 = 3.7 and 2.0 nM for rat and mouse SGLT2, respectively). Canagliflozin inhibits 14 C-AMG uptake in CHO-hSGLT1 and mSGLT1 cells with IC 50 of 684±159 nM and >1,000 nM, respectively.
Canagliflozin (30 mg/kg treatment for 4 weeks) reduced blood glucose (BG) levels, respiratory exchange ratio, and body weight gain in DIO mice.
Canagliflozin (3 mg/kg for 3 weeks) increases urinary glucose excretion (UGE) with no significant change in total food intake compared with that in vehicle-treated rats, leading to a decrease in body weight In ZF rats.
Animal Model: | Diet-induced obese, insulin resistantmice (DIO) Mice |
Dosage: | 30 mg/kg |
Administration: | Oral gavage; daily; 4 weeks |
Result: | Reduced BG levels, respiratory exchange ratio, and body weight gain. |
Animal Model: | Male Zucker fatty (ZF) obese, insulin resistant rats |
Dosage: | 3 mg/kg |
Administration: | Oral gavage; daily; 3 weeks |
Result: | UGE was increased with no significant change in total food intake compared with that in vehicle-treated rats, leading to a decrease in body weight. |