5’-Adenosine monophosphate activated protein kinase (AMPK) is a key upstream regulator of numerous signaling pathways involved in cellular energy homeostasis and is thought to mediate some of the beneficial effects of exercise, making it an attractive target for the potential treatment of Type II Diabetes Mellitis. As a heterotrimeric enzyme, AMPK is composed of a catalytic α-subunit (2 isoforms), a β-subunit (2 isoforms), and a regulatory γ-subunit (3 isoforms) and is expressed as 12 isoforms that are differentially distributed across tissue types within the body and across species. Long-acting allosteric pan-AMPK activators, as exemplified by MK-8722, have demonstrated robust glucose lowering in both acute and chronic efficacy models, but have also caused cardiac hypertrophy. We hypothesized that the hypertrophy was the result of excessive pharmacology of AMPK activation and that transient AMPK activation, as opposed to sustained activation, would more closely mimic moderate daily exercise by providing glucose lowering without producing cardiac hypertrophy. Herein we describe the derivatization of the terminal phenyl moiety of MK-8722 to modulate physiochemical properties and identify short-acting, potent pan-AMPK activators.

Short acting pan-AMPK activators as exercise mimetics

255th National Meeting (2018)

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