AMG-3969 is a potent glucokinase-glucokinase regulatory protein interaction ( GK-GKRP ) disruptor with an IC 50 of 4 nM.
In Vitro
AMG-3969 exhibits potent cellular activity with an EC 50 of 0.202 μM and IC 50 of 4 nM,. It potently reverses the inhibitory effect of GKRP on GK activity and promotes GK translocation in vitro (isolated hepatocytes). MCE has not independently confirmed the accuracy of these methods. They are for reference only.
In Vivo
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. MCE has not independently confirmed the accuracy of these methods. They are for reference only.
Animal administration
Mice: 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 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 μL sample of whole blood is analyzed for drug exposure . aladdin has not independently confirmed the accuracy of these methods. They are for reference only.
IC50& Target:IC50: 4 nM (GK-GKRP)
