AMPK is considered as a potential high value target for metabolic disorders. Here, we present the molecular modeling, in vitro and in vivo characterization of Activator-3, 2-[2-(4-(trifluoromethyl)phenylamino)thiazol-4-yl]acetic acid, an AMP mimetic and a potent pan-AMPK activator. Activator-3 and AMP likely share common activation mode for AMPK activation. Activator-3 enhanced AMPK phosphorylation by upstream kinase LKB1 and protected AMPK complex against dephosphorylation by PP2C. Molecular modeling analyses followed by in vitro mutant AMPK enzyme assays demonstrate that Activator-3 interacts with R70 and R152 of the CBS1 domain on AMPK γ subunit near AMP binding site. Activator-3 and C2, a recently described AMPK mimetic, bind differently in the γ subunit of AMPK. Activator-3 unlike C2 does not show cooperativity of AMPK activity in the presence of physiological concentration of ATP (2 mM). Activator-3 displays good pharmacokinetic profile in rat blood plasma with minimal brain penetration property. Oral treatment of High Sucrose Diet (HSD) fed diabetic rats with 10 mg/kg dose of Activator-3 once in a day for 30 days significantly enhanced glucose utilization, improved lipid profiles and reduced body weight, demonstrating that Activator-3 is a potent AMPK activator that can alleviate the negative metabolic impact of high sucrose diet in rat model.

中文翻译：

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2- [2-（4-（三氟甲基）苯基氨基）噻唑-4-基]乙酸（活化剂-3）是AMPK的有效活化剂。

AMPK被认为是代谢紊乱的潜在高价值目标。在这里，我们介绍了Activator-3、2- [2-（4-（三氟甲基）苯基氨基）噻唑-4-基]乙酸，AMP模拟物和有效的pan-AMPK的分子模型，体外和体内表征激活剂。Activator-3和AMP可能共享AMPK激活的通用激活模式。激活剂3增强了上游激酶LKB1引起的AMPK磷酸化，并保护了AMPK复合物免受PP2C的去磷酸化作用。分子模型分析，然后进行体外突变AMPK酶测定，表明Activator-3与AMP结合位点附近AMPKγ亚基上CBS1域的R70和R152相互作用。最近描述的AMPK模拟物Activator-3和C2在AMPK的γ亚基中的结合不同。与C2不同，激活剂3在存在生理浓度的ATP（2 mM）的情况下不显示AMPK活性的协同作用。Activator-3在大鼠血浆中显示出良好的药代动力学特征，具有最小的脑渗透特性。每天口服10毫克/千克剂量的Activator-3给予糖尿病大鼠高蔗糖饮食（HSD）口服治疗，持续30天，可显着提高葡萄糖利用率，改善脂质状况和减轻体重，表明Activator-3是有效的AMPK激活剂可减轻高蔗糖饮食对大鼠模型的负面代谢影响。