1 research outputs found
Discovery of MK-8722: A Systemic, Direct Pan-Activator of AMP-Activated Protein Kinase
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