928672-86-0
928672-86-0 結構式
基本信息
半水卡格列嗪
坎格列嗪半水物
卡格列凈半水物
卡格列凈半水合物
坎格列凈(半水)
坎格列嗪半水合物
坎格列凈半水合物
坎格列凈半水化合物
卡格列凈半水化合物
TA7284 hemihydrate
TA-7284 hemihydrate
Invokana hemihydrate
Canagliflozin hydrate
Cagliflozin heMihydrate
JNJ28431754 hemihydrate
JNJ 28431754 hemihydrate
JNJ-28431754 hemihydrate
Canagliflozin heMihydrate
物理化學性質
常見問題列表
以T-1095為基礎，許多藥廠都在圍繞T-1095衍生物開發(fā)SGLT-2抑制劑糖尿病藥物。日本三菱的化學家，圍繞C-葡萄糖苷及N-葡萄糖苷展開了研究，目標就是要開發(fā)出針對SGLT-2抑制劑的藥物。
研究結果初步顯示，聯(lián)苯結構的C-葡萄糖苷的化合物抑制活性較弱；相反，芐基苯胺的N-葡萄糖苷的化合物展現(xiàn)出強的體外抑制活性，但是N-葡萄糖苷的代謝穩(wěn)定性相對還是較差。因此，后續(xù)合成了一系列芳環(huán)C-葡萄糖苷和硫唑嘌呤芳香N-葡萄糖苷化合物，并比較了相關化合物的活性及尿排糖量，結果如下：
通過上述數(shù)據(jù)可以看出，IC50顯示，化合物20及化合物21的活性表現(xiàn)出較為明顯的優(yōu)勢；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-葡萄糖苷化合物中體現(xiàn)出最高的效能；對于R1的取代，鹵素和短鏈烷烴較氫原子展現(xiàn)出更高的體外活性；體內效能和化學穩(wěn)定性方面，R2的取代基團為芳基要優(yōu)于烷基或者鹵素基團。因此，最終選擇化合物21為目標化合物進一步進行研究，也就是未來的坎格列凈 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. |