1 research outputs found
Hit-to-Lead Optimization and Discovery of 5‑((5-([1,1′-Biphenyl]-4-yl)-6-chloro‑1<i>H</i>‑benzo[<i>d</i>]imidazol-2-yl)oxy)-2-methylbenzoic Acid (MK-3903): A Novel Class of Benzimidazole-Based Activators of AMP-Activated Protein Kinase
AMP-activated protein kinase (AMPK)
plays an essential role as
a cellular energy sensor and master regulator of metabolism in eukaryotes.
Dysregulated lipid and carbohydrate metabolism resulting from insulin
resistance leads to hyperglycemia, the hallmark of type 2 diabetes
mellitus (T2DM). While pharmacological activation of AMPK is anticipated
to improve these parameters, the discovery of selective, direct activators
has proven challenging. We now describe a hit-to-lead effort resulting
in the discovery of a potent and selective class of benzimidazole-based
direct AMPK activators, exemplified by 5-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1<i>H</i>-benzoÂ[<i>d</i>]Âimidazol-2-yl)Âoxy)-2-methylbenzoic
acid, <b>42</b> (MK-3903). Compound <b>42</b> exhibited
robust target engagement in mouse liver following oral dosing, leading
to improved lipid metabolism and insulin sensitization in mice