Discovery of MK-8722: A Systemic, Direct Pan-Activator of AMP-Activated Protein Kinase.

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.

• Authors: Danqing Feng, Tesfaye Biftu, F Anthony Romero, Ahmet Kekec, James Dropinski, Andrew Kassick, Shiyao Xu, Marc M Kurtz, Anantha Gollapudi, Qing Shao, Xiaodong Yang, Ku Lu, Gaochao Zhou, Daniel Kemp, Robert W Myers, Hong-Ping Guan, Maria E Trujillo, Cai Li, Ann Weber, Iyassu K Sebhat
• Journal: ACS medicinal chemistry letters (ACS Med Chem Lett) Vol. 9 Issue 1 Pg. 39-44 (Jan 11 2018) ISSN: 1948-5875 [Print] United States
• PMID: 29348809 (Publication Type: Journal Article)