| 產品描述： | AMG-3969 is an effective glucokinase-glucokinase regulatory protein interaction (GK-GKRP) disruptor (IC50: 4 nM). |
| 靶點： |
Glucokinase |
| 體外研究： |
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). |
| 體內研究： |
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. |
| 動物實驗： |
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 . |
| 參考文獻： |
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 |
| 保存條件： |
-20℃ |
| 配置溶液濃度參考： |
|
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： |
部分產品我司僅能提供部分信息，我司不保證所提供信息的權威性，僅供客戶參考交流研究之用。 |
上海工商
危險品化學品經營許可證（不帶存儲）
營業執照(三證合一)
北京