2 research outputs found
Synthesis of Fluorinated and Nonfluorinated Tebufenpyrad Analogues for the Study of Anti-angiogenesis MOA
In this contribution we report the
synthesis of fluorinated and
nonfluorinated tebufenpyrad analogues to explore potential druglike
properties through the phenotypic screening as part of the Lilly Open
Innovation Drug Discovery (OIDD) program
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>-benzo[<i>d</i>]imidazol-2-yl)oxy)-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