5’-adensoine monophosphate-activated protein kinase (AMPK) is known to regulate pathways involved in glucose and lipid metabolism in liver, muscle, and adipose tissue. As a key mechanism for responding to cellular energy levels, pharmacological activation of AMPK represents a potential target for the treatment of type 2 diabetes mellitus (T2DM) and other metabolic diseases. Maximal efficacy was hypothesized to be observed from a pan-AMPK activator with balanced exposure between liver and muscle tissue. Previous aromatic acids favored distribution in liver tissue of mice and demonstrated limited muscle exposure. To maximize efficacy, development of MK-8722 focused on a more balanced liver to muscle ratio, pan-AMPK activation profile, and improvements in half-life. This poster will describe structural changes to the terminal ether linked ring system to modulate these properties and improve systemic exposure. MK-8722 displayed robust glucose lowering in both acute and chronic efficacy models to improve glucose homeostasis, but induced cardiac hypertrophy.

Evolution of AMPK activators with improved muscle exposure

255th National Meeting (2018)

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