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

GK-GKRP:4 nM (cell free)

AMG-3969 demonstrates significant cellular activity (EC50: 0.202 μM; IC50: 4 nM) [1,2], reversing GKRP's inhibitory effect on GK activity and promoting GK translocation in vitro (isolated hepatocytes) [3].

AMG-3969, at a dosage of 100 mg/kg, significantly lowers blood glucose levels, achieving a 56% reduction eight hours post-administration [1]. This compound effectively normalizes blood glucose levels across various rodent diabetes models and exhibits favorable in vivo pharmacokinetic properties in rats (75%). It also progressively reduces blood glucose levels in db/db mice in a dose-responsive manner [2]. Demonstrating efficacy across three diabetes models—diet-induced obese (DIO), ob/ob, and db/db mice, AMG-3969, however, does not impact blood glucose in normoglycemic C57BL/6 (B6) mice. Additionally, it is highly efficient in enhancing carbohydrate metabolism, leading to noticeable prolonged effects on carbohydrate oxidation, evident from the increased respiratory exchange ratio observed up to the following day post a single administration [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].