In Vitro Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, USA.
Biology-Discovery, Merck Research Laboratories, Kenilworth, NJ 07033, USA.
Science. 2017 Aug 4;357(6350):507-511. doi: 10.1126/science.aah5582. Epub 2017 Jul 13.
5'-Adenosine monophosphate-activated protein kinase (AMPK) is a master regulator of energy homeostasis in eukaryotes. Despite three decades of investigation, the biological roles of AMPK and its potential as a drug target remain incompletely understood, largely because of a lack of optimized pharmacological tools. We developed MK-8722, a potent, direct, allosteric activator of all 12 mammalian AMPK complexes. In rodents and rhesus monkeys, MK-8722-mediated AMPK activation in skeletal muscle induced robust, durable, insulin-independent glucose uptake and glycogen synthesis, with resultant improvements in glycemia and no evidence of hypoglycemia. These effects translated across species, including diabetic rhesus monkeys, but manifested with concomitant cardiac hypertrophy and increased cardiac glycogen without apparent functional sequelae.
5'-腺嘌呤单核苷酸激活的蛋白激酶（AMPK）是真核生物能量平衡的主要调节剂。尽管经过三十年的研究，AMPK 的生物学作用及其作为药物靶点的潜力仍未完全了解，主要是因为缺乏优化的药理学工具。我们开发了 MK-8722，一种有效的、直接的、别构的 12 种哺乳动物 AMPK 复合物的激活剂。在啮齿动物和恒河猴中，MK-8722 介导的骨骼肌 AMPK 激活导致强烈、持久、胰岛素非依赖性的葡萄糖摄取和糖原合成，从而改善血糖，且没有低血糖的证据。这些作用在不同物种中都有体现，包括糖尿病恒河猴，但表现为伴有心脏肥大和增加的心脏糖原，而没有明显的功能后遗症。
