2 research outputs found
Structure-Based Design of ASK1 Inhibitors as Potential Agents for Heart Failure
Apoptosis
signal-regulating kinase 1 (ASK1/MAP3K) is a mitogen-activated
protein kinase family member shown to contribute to acute ischemia/reperfusion
injury. Using structure-based drug design, deconstruction, and reoptimization
of a known ASK1 inhibitor, a lead compound was identified. This compound
displayed robust MAP3K pathway inhibition and reduction of infarct
size in an isolated perfused heart model of cardiac injury
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