MK-3903 is a potent AMPK activator with EC50 value of 9nM and max AMP activation of 320%. MK-3903 exhibited effect on recombinant human pAMPK complexes α1 β1 γ1, α1 β1 γ2, α1 β1 γ3, α1 β2 γ1, α1 β2 γ2, α1 β2 γ3, α2 β1 γ1, α2 β1 γ2, α2 β1 γ3, α2 β2 γ1, α2 β2 γ2 and α2 β2 γ3 units with EC50 value/max (%) of 8nM/217%, 21nM/242%, 19nM/61%, 40nM/50%, 118nM/36%, 2860nM/8%, 9nM/320%, 22nM/175%, 26nM/209%, 39nM/94%, 23nM/145% and 35nM/135%, respectively. Oral administration of MK-3903 at dose of 30mg/kg, BID, for 15days significantly increased the level of phosphorylated ACC, a downstream AMPK substrate as an indicator of intracellular AMPK activation, in liver and muscle of diet-induced obese mice. The hepatic fatty acid synthesis was inhibited by 29%, 37% and 49% in db/+mice dosed of 3, 10 and 30mg/kg MK-3903 post 8h. Oral dose of 10 and 30mg/kg MK-3903, BID, for 12 days resulted reduction of insulin resistance index of diet-induced obese mice up to 35% and 64% in an oral glucose tolerance test.
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