| 产品描述： | AMG-3969 is an effective glucokinase-glucokinase regulatory protein interaction (GK-GKRP) disruptor (IC50: 4 nM). |
| 靶点： |
Glucokinase |
| 体外研究： |
AMG-3969 exhibits potent cellular activity with an EC50 of 0.202 μM and IC50 of 4 nM. It potently reverses the inhibitory effect of GKRP on GK activity and promotes GK translocation in vitro (isolated hepatocytes). |
| 体内研究： |
AMG-3969 has good in vivo pharmacokinetic (PK) properties in rats (75%) and significantly lowers blood glucose levels in a dose-dependent manner db/db mice. AMG-3969 (100 mg/kg) demonstrates significant reductions in blood glucose with robust efficacy (56% reduction) observed at the 8 h time point. AMG-3969 demonstrates dose-dependent efficacy in three models of diabetes: diet induced obese (DIO), ob/ob and db/db mice; however,AMG-3969 is ineffective in lowering blood glucose in normoglycaemic C57BL/6 (B6) mice. AMG-3969 is highly effective in promoting carbohydrate substrate. AMG-3969 exhibits extended changes to carbohydrate oxidation as observed by increased respiratory exchange ratio into the next night and day after a single dose. |
| 动物实验： |
Diabetic db/db mice are used in the study. At 8:00 AM, mice are bled via retro-orbital sinus puncture and blood glucose values are determined and used to randomize the animals in which their averages are similar, and only mice with blood glucose ranges between 300 and 500 mg/dL are included. Vehicle (2% hydroxypropyl methylcellulose, 1% Tween 80, pH 2.2 adjusted with MSA) or AMG-3969 (10, 30, 100 mg/kg) are gavaged at 9:00 AM. Blood glucose is measured at 4, 6, or 8 h posttreatment. At each time point, a 15 μL sample of whole blood is analyzed for drug exposure . |
| 参考文献： |
1. Lloyd DJ, et al. Antidiabetic effects of glucokinase regulatory protein small-molecule disruptors. Nature. 2013 Dec 19;504(7480):437-40. 2. Nishimura N, et al. Small molecule disruptors of the glucokinase-glucokinase regulatory protein interaction: 3. Structure-activity relationships within the aryl carbinol region of the N-arylsulfonamido-N'-arylpiperazine series. J Med Chem. 2014 Apr 10;57(7):3094-116. 3. St Jean DJ Jr, et al. Small molecule disruptors of the glucokinase-glucokinase regulatory protein interaction: 2. Leveraging structure-based drug design to identify analogues with improved pharmacokinetic profiles. J Med Chem. 2014 Jan 23;57(2):325-38. |
| 溶解性： |
Soluble in DMSO |
| 保存条件： |
-20℃ |
| 配置溶液浓度参考： |
|
1mg |
5mg |
10mg |
| 1 mM |
1.914 ml |
9.57 ml |
19.14 ml |
| 5 mM |
0.383 ml |
1.914 ml |
3.828 ml |
| 10 mM |
0.191 ml |
0.957 ml |
1.914 ml |
| 50 mM |
0.038 ml |
0.191 ml |
0.383 ml |
|
| 注意： |
部分产品我司仅能提供部分信息，我司不保证所提供信息的权威性，仅供客户参考交流研究之用。 |
上海工商
危险品化学品经营许可证（不带存储）
营业执照(三证合一)
北京