AMG-3969 - GK-GKRP Disruptor - 生命科學(xué)試劑 - MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEAMG-3969Cat. No.: HY-12411CAS No.: 1361224-53-4分式: CHFNOS分量: 522.46作靶點(diǎn): Glucokinase作通路: Metabolic Enzyme/Protease儲存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性數(shù)據(jù)體外實(shí)驗(yàn) DMSO : 100 mg/mL (191.40 mM)* means

2、 soluble, but saturation unknown.Mass Solvent1 mg 5 mg 10 mg Concentration制備儲備液1 mM 1.9140 mL 9.5701 mL 19.1402 mL5 mM 0.3828 mL 1.9140 mL 3.8280 mL10 mM 0.1914 mL 0.9570 mL 1.9140 mL請根據(jù)產(chǎn)品在不同溶劑中的溶解度，選擇合適的溶劑配制儲備液，并請注意儲備液的保存式和期限。體內(nèi)實(shí)驗(yàn)請根據(jù)您的實(shí)驗(yàn)動物和給藥式選擇適當(dāng)?shù)娜芙獍?，配制前請先配制澄的儲備液，再依次添加助溶?為保證實(shí)驗(yàn)結(jié)果的可靠性，體內(nèi)實(shí)驗(yàn)的作液，建議您現(xiàn)現(xiàn)

3、配，當(dāng)天使；澄的儲備液可以根據(jù)儲存條件，適當(dāng)保存；以下溶劑前的百分 指該溶劑在您配制終溶液中的體積占)：1. 請依序添加每種溶劑： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 2.5 mg/mL (4.79 mM); Clear solution2. 請依序添加每種溶劑： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 2.5 mg/mL (4.79 mM); Clear solution3. 請依序添加每種溶劑： 10% DMSO 90% corn oil1/2 Master of

4、Small Molecules 您邊的抑制劑師www.MedChemESolubility: 2.5 mg/mL (4.79 mM); Clear solutionBIOLOGICAL ACTIVITY物活性 AMG-3969有效的葡萄糖激酶-葡糖激酶調(diào)節(jié)蛋(GK-GKRP)相互作的擾物，IC50值為4 nM。IC50 & Target IC50: 4 nM (GK-GKRP) 1體外研究 AMG-3969 exhibits potent cellular activity with an EC50 of 0.202 M and IC50 of 4 nM 1, 2. It potentlyre

5、verses the inhibitory effect of GKRP on GK activity and promotes GK translocation in vitro (isolatedhepatocytes) 3.體內(nèi)研究 AMG-3969 has good in vivo pharmacokinetic (PK) properties in rats (75%) and significantly lowers bloodglucose levels in a dose-dependent manner db/db mice 1. AMG-3969 (100 mg/kg) d

6、emonstrates significantreductions in blood glucose with robust efficacy (56% reduction) observed at the 8 h time point 2. AMG-3969 demonstrates dose-dependent efficacy in three models of diabetes: diet induced obese (DIO), ob/oband db/db mice; however,AMG-3969 is ineffective in lowering blood glucos

7、e in normoglycaemic C57BL/6(B6) mice. AMG-3969 is highly effective in promoting carbohydrate substrate. AMG-3969 exhibits extendedchanges to carbohydrate oxidation as observed by increased respiratory exchange ratio into the next nightand day after a single dose 3.PROTOCOLAnimal Mice: Diabetic db/db

8、 mice are used in the study. At 8:00 AM, mice are bled via retro-orbital sinus punctureAdministration 2 and blood glucose values are determined and used to randomize the animals in which their averages aresimilar, and only mice with blood glucose ranges between 300 and 500 mg/dL are included. Vehicl

9、e (2%hydroxypropyl methycellulose, 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 Lsample of whole blood is analyzed for drug exposure 2.MCE has not independently confirme

10、d the accuracy of these methods. They are for reference only.REFERENCES1. 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

11、 protein interaction: 3. Structure-activityrelationships 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.McePdfHeightCaution: Product h