5′-Adenosine monophosphate-activated protein kinase (AMPK) is a key regulator of mammalian energy homeostasis and has been implicated in mediating many of the beneficial effects of exercise and weight loss including lipid and glucose trafficking. As such, the enzyme has long been of interest as a target for the treatment of Type 2 Diabetes Mellitus. We describe the optimization of β1-selective, liver-targeted AMPK activators and their evolution into systemic pan-activators capable of acutely lowering glucose in mouse models. Identifying surrogates for the key acid moiety in early generation compounds proved essential in improving β2-activation and in balancing improvements in plasma unbound fraction while avoiding liver sequestration.

中文翻译：

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MK-8722的发现：AMP激活的蛋白激酶的系统性，直接泛激活剂

5'-腺苷单磷酸激活蛋白激酶（AMPK）是哺乳动物能量稳态的关键调节剂，与调解运动和减肥（包括脂质和葡萄糖运输）的许多有益作用有关。因此，作为治疗2型糖尿病的靶标，长期以来一直对该酶感兴趣。我们描述了β1选择性，肝靶向的AMPK激活剂的优化，以及它们向系统性泛激活剂的进化，能够在小鼠模型中急剧降低葡萄糖。鉴定出早期化合物中关键酸部分的替代物对于改善β2活化和平衡血浆未结合部分的改善，同时避免肝脏螯合至关重要。