AMG-3969is a potent glucokinase-glucokinase regulatory protein interaction (GK-GKRP) disruptor. Itcan strongly boost the dissociation of the GK-GKRP complex and promote GK translocation in-vivo. In rodent model of diabetes, AMG-3969 reduces blood glucose levels without affecting euglycemic animals. It is a promising drug for the treatment of type II diabetes through lowering blood glucose levels with reduced potential for hypoglycaemic risk.
AMG-3969 is a potent glucokinase-glucokinase regulatory protein interaction (GK-GKRP) disruptor with an IC50 of 4 nM.
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[1]. AMG-3969 (100 mg/kg) demonstrates significant reductions 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/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].
Lloyd, David J., et al. "Antidiabetic effects of glucokinase regulatory protein small-molecule disruptors." Nature 504.7480(2013):437-40.
Bourbeau, M. P., et al. "Nonracemic synthesis of GK-GKRP disruptor AMG-3969. " Synfacts 79.8(2014):3684.
http://www.metonchem.com/products/amg-3969-cas1361224-53-4/
