MK-8722的发现：一种全身性的、直接的AMP激活蛋白激酶泛激活剂。
Discovery of MK-8722: A Systemic, Direct Pan-Activator of AMP-Activated Protein Kinase.
作者信息
Feng Danqing, Biftu Tesfaye, Romero F Anthony, Kekec Ahmet, Dropinski James, Kassick Andrew, Xu Shiyao, Kurtz Marc M, Gollapudi Anantha, Shao Qing, Yang Xiaodong, Lu Ku, Zhou Gaochao, Kemp Daniel, Myers Robert W, Guan Hong-Ping, Trujillo Maria E, Li Cai, Weber Ann, Sebhat Iyassu K
机构信息
Medicinal Chemistry, PPDM Preclinical ADME, In Vitro Pharmacology, In Vivo Pharmacology, and Biology-Discovery Departments, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
出版信息
ACS Med Chem Lett. 2017 Dec 1;9(1):39-44. doi: 10.1021/acsmedchemlett.7b00417. eCollection 2018 Jan 11.
Abstract
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.
摘要
5'-单磷酸腺苷激活蛋白激酶（AMPK）是哺乳动物能量稳态的关键调节因子，在介导运动和减肥的许多有益作用（包括脂质和葡萄糖转运）中发挥作用。因此，长期以来，该酶一直是治疗2型糖尿病的靶点。我们描述了β1选择性、肝脏靶向性AMPK激活剂的优化及其向能够在小鼠模型中急性降低血糖的全身性泛激活剂的演变。事实证明，在早期化合物中确定关键酸性部分的替代物对于改善β2激活、平衡血浆游离分数的提高以及避免肝脏滞留至关重要。
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本文引用的文献
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