AMP-activated protein kinase (AMPK) plays an essential role as a cellular energy sensor and master regulator of metabolism in eukaryotes. Dysregulated lipid and carbohydrate metabolism resulting from insulin resistance leads to hyperglycemia, the hallmark of type 2 diabetes mellitus (T2DM). While pharmacological activation of AMPK is anticipated to improve these parameters, the discovery of selective, direct activators has proven challenging. We now describe a hit-to-lead effort resulting in the discovery of a potent and selective class of benzimidazole-based direct AMPK activators, exemplified by 5-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid, 42 (MK-3903). Compound 42 exhibited robust target engagement in mouse liver following oral dosing, leading to improved lipid metabolism and insulin sensitization in mice.

中文翻译：

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5-（（5-（[（1,1'-联苯] -4-基）-6-氯-1 H-苯并[ d ]咪唑-2-基）氧基）的命中优化和发现2-甲基苯甲酸（MK-3903）：新型的基于苯并咪唑的AMP活化蛋白激酶活化剂

AMP激活的蛋白激酶（AMPK）作为细胞能量传感器和真核生物代谢的主要调节剂，起着至关重要的作用。由胰岛素抵抗引起的脂质和碳水化合物代谢失调导致高血糖症，这是2型糖尿病（T2DM）的标志。虽然预期AMPK的药理学活化会改善这些参数，但事实证明，发现选择性，直接活化剂具有挑战性。现在，我们描述了铅到铅的努力，导致发现了基于苯并咪唑的有效和选择性类别的直接AMPK活化剂，示例为5-（（5-（[[1,1'-biphenyl] -4-yl） -6-氯-1 H-苯并[ d ]咪唑-2-基）氧基）-2-甲基苯甲酸42（MK-3903）。化合物42 口服给药后，小鼠肝脏表现出强大的靶标参与性，从而改善了小鼠的脂质代谢和胰岛素敏感性。