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CAS No.: 1361224-53-4

AMG3969 Catalog No. CSN21071

Synonyms: AMG-3969

AMG-3969 is a glucokinase-GKRP disruptor with IC50 value of 343nM and potently reverses the inhibitory effect of GKRP on GK activity.

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400-920-2911

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纯度 & 质量文件批次:

靶点选择性

生物活性

实验方案

技术信息

生物活性

描述Glucokinase (GK) is a key enzyme in regulation of glucose homeostasis. It regulates glucose uptake and glycogen synthesis, suppresses glucose production through converting glucose to glucose-6-phosphate2,3 in pancreatic β-cells, liver hepatocytes, specific hypothalamic neurons, and gut enterocytes. GKRP, the main regulator of glucokinase, could inactivate and sequester glucokinase by removing glucokinase from the gluconeogenic process and prevents a futile cycle of glucose phosphorylation. AMG-3969 is a glucokinase-GKRP disruptor with IC50 value of 343nM in AlphaScreen binding assay, and potently reverses the inhibitory effect of GKRP on GK activity. Oral administration of AMG-3969 at dose of 100mg/kg lowered blood glucose levels in rodent models restricted to diabetic and not normoglycaemic animals, which is different with glucokinase activator. A pharmacodynamic response of AMG-3969 as promotion of glucokinase translocation could be observed both in vivo and in vitro after AMG-3969 treatment.
作用机制AMG-3969 may bind to a previously unknown binding pocket in GKRP distinct from that of the phosphofructose-binding site.^[1]

动物研究

剂量

Rat: 2 mg/kg^[3] (i.v.); 10 mg/kg^[3] (p.o.) Mice: 2 mg/kg^[3] (i.v.); 10 mg/kg^[3] (p.o.)

给药途径

i.v., p.o.

动物药代数据

Animal	Mice^[3]	Rats^[3]
Dose	2 mg/kg (i.v.) 10 mg/kg (p.o.)	2 mg/kg (i.v.) 10 mg/kg (p.o.)
Administration	i.v. p.o.	i.v. p.o.
F	40% (p.o.)	75% (p.o.)
T_1/2	6.7 h (i.v.)	3.6 h (i.v.)
T_max	5.0 h (p.o.)
CL	0.11 L/kg/h (i.v.)	0.75 L/kg/h (i.v.)
C_max	5.82 μM (p.o.)
AUC	64.8 μM·h (p.o.)	20.0 μM·h (p.o.)

参考文献

[1] Lloyd DJ, St Jean DJ Jr, et al. Antidiabetic effects of glucokinase regulatory protein small-molecule disruptors. Nature. 2013 Dec 19;504(7480):437-40.
[2] St Jean DJ Jr, Ashton KS, 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.
[3] Nishimura N, Norman MH, 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.

实验方案

计算器摩尔计算器总药量计算器工作液计算器
储存液制备
- 1 mg
- 5 mg
- 10 mg
- 1 mM
- 1.9140 mL
- 9.5701 mL
- 19.1402 mL
- 5 mM
- 0.3828 mL
- 1.9140 mL
- 3.8280 mL
- 10 mM
- 0.1914 mL
- 0.9570 mL
- 1.9140 mL

技术信息

CAS号

1361224-53-4

储存条件

粉末: Keep in dark place,Sealed in dry,2-8°C

液体: -20°C:3-6 月 -80°C:12月

分子式

C21H20F6N4O3S

运输

蓝冰

分子量

522.46

别名

AMG-3969

溶解度

DMSO	100.0 mg/mL (191.4 mM)

动物实验配方

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