AMPK synthetic activators

National Center For Advancing Translational Sciences

Investigators

Abstract

During this period the collaborative team has worked to characterize a number of small molecule hits previously found to activate 5' adenosine monophosphate-activated protein kinase (AMPK). The team has optimized select chemotypes via medicinal chemistry efforts and implemented a novel high-throughput mass spectrometry assay to measure cholesterol to test activity of the compounds. Top actives were tested in the context of Niemann Pick C, a lysosomal storage disease characterized by cholesterol accumulation. The team is utilizing mass spectrometry data to evaluate several small molecules originally obtained by virtual screening. One of the chemotype was selected of optimization, and after a long structure activity relationship campaign we obtained a potent, and selective AMPK agonists able to normalize the phenotype of NPC progenitor CNS neurons without inducing cell death. Several molecules were selected for pharmacokinetics, with some of them displaying good brain exposure. An optimized candidate has been selected for additional in vivo efficacy studies.