Discovery of MK-8722: A Systemic, Direct Pan-Activator of AMP-Activated Protein Kinase
| Autor: | F. Anthony Romero, Robert W. Myers, Hong-Ping Guan, Anantha Gollapudi, Gaochao Zhou, Ku Lu, James F. Dropinski, Marc M. Kurtz, Xiaodong Yang, Cai Li, Iyassu K. Sebhat, Tesfaye Biftu, Danqing Feng, Ahmet Kekec, Ann E. Weber, Qing Shao, Daniel M. Kemp, Andrew Kassick, Shiyao Xu, Maria E. Trujillo |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
chemistry.chemical_classification biology Activator (genetics) Organic Chemistry Regulator AMPK Type 2 Diabetes Mellitus Biochemistry Energy homeostasis Cell biology 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Enzyme chemistry AMP-activated protein kinase Drug Discovery biology.protein Protein kinase A 030217 neurology & neurosurgery |
| Zdroj: | ACS Medicinal Chemistry Letters. 9:39-44 |
| ISSN: | 1948-5875 |
| DOI: | 10.1021/acsmedchemlett.7b00417 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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