MK-3903

An AMPK activator

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Background

MK-3903 is an activator of AMP-activated protein kinase (AMPK; EC₅₀ = 9 nM).¹ It is selective for AMPK over a kinase panel at 10 ?M, as well as the cytochrome P450 (CYP) isoforms CYP3A4 and CYP2D6 (IC₅₀s = >50 ?M for both) and the pregnane X receptor (PXR; EC₅₀ = >30 ?M). MK-3903 (30 mg/kg) increases muscle and liver levels of phosphorylated ACC, an AMPK substrate, and reduces insulin resistance in diet-induced obese (DIO) mice. It inhibits hepatic fatty acid synthesis in db/db mice when administered at doses ranging from 3 to 30 mg/kg.

1.Lan, P., Romero, F.A., Wodka, D., et al.Hit-to-lead optimization and discovery of 5-((5-([1,1'-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid (MK-3903): A novel class of benzimidazole-based activators of AMP-activated protein kinaseJ. Med. Chem.60(21)9040-9052(2017)

Protocol

Kinase experiment:

The enzymatic reaction is performed. Briefly, the AMPK complex of interest is appropriately diluted in AMPK reaction buffer and incubated at room temperature for 30 min to yield pAMPK. Then, MK-3903 (compound 42) and pAMPK are pre-incubated by adding appropriately diluted MK-3903 in DMSO (1.2 μL total) to the reaction buffer containing pAMPK (15 μL per well), the plate is vortexed briefly and then incubated at room temperature for 30 min. The plate is sealed and incubated at room temperature for 60 min, at which time the reaction is stopped by the addition of quench buffer. EC50s and %activation parameters are calculated from %product vs. activator concentration plots[1].

Animal experiment:

DIO mice at 17 weeks of age are used in this study. Mice are conditioned to dosing with vehicle (5% Tween 80, 0.25% methylcellulose, 0.02% SDS) at 5 mL/kg BID for 5 days. At that time, mice are bled, glucose and insulin measured and the animals sorted into treatment groups based on glucose, insulin and body weight. Each group of animals receives administration of MK-3903 (compound 42) in vehicle at 3 mg/kg, 10 mg/kg, 30 mg/kg, or vehicle alone for 12-day BID. Another group of mice receiving MK-3903 with vehicle at 30 mg/kg for 12-day QD is included as well. Food intake and body weight are measured daily[1].

参考文献:

[1]. Lan P, Romero FA, et al. Hit-to-Lead Optimization and Discovery of 5-((5-([1,1'-Biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic Acid (MK-3903): A Novel Class of Benzimidazole-Based Activators of AMP-Activated Protein Kinase. J Med Chem. 2017 Nov 9;60(21):9040-9052.