AMG-3969 是一种葡萄糖激酶-葡糖激酶调节蛋白相互作用的干扰物，IC50=为4 nM。

AMG-3969 is an effective glucokinase-glucokinase regulatory protein interaction (GK-GKRP) disruptor (IC50: 4 nM).

AMG-3969 exhibits potent cellular activity (EC50: 0.202 μM; IC50: 4 nM) [1,2]. AMG-3969 effectively reverses the inhibitory effect of GKRP on GK activity and promotes GK translocation in vitro (isolated hepatocytes) [3].

AMG-3969 (100 mg/kg) demonstrates significant reductions in blood glucose with robust efficacy (56% reduction) observed at the 8 h time point [1]. AMG-3969 normalized blood glucose levels in several rodent models of diabetes. 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 [2]. 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 [3].

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 [1].

1361224-53-4

C21H20F6N4O3S

522.46

DMSO:100 mg/mL (191.40 mM)
Powder: -20°C for 3 years
In solvent: -80°C for 2 years