Discovery of new acylaminopyridines as GSK-3 inhibitors by a structure guided in-depth exploration of chemical space around a pyrrolopyridinone core.

Abstract

Glycogen synthase kinase-3 (GSK-3) has been proposed to play a crucial role in the pathogenesis of many diseases including cancer, stroke, bipolar disorders, diabetes and neurodegenerative diseases. GSK-3 inhibition has been a major area of pharmaceutical interest over the last two decades. A plethora of reports appeared recently on selective inhibitors and their co-crystal structures in GSK-3β. We identified several series of promising new GSK-3β inhibitors from a coherent design around a pyrrolopyridinone core structure. A systematic exploration of the chemical space around the central spacer led to potent single digit and sub-nanomolar GSK-3β inhibitors. When dosed orally in a transgenic mouse model of Alzheimer's disease (AD), an exemplary compound showed significant lowering of Tau phosphorylation at one of the GSK-3 phosphorylating sites, Ser396. X-ray crystallography greatly aided in validating the binding hypotheses.

• Authors: Prasanna Sivaprakasam, Xiaojun Han, Rita L Civiello, Swanee Jacutin-Porte, Kevin Kish, Matt Pokross, Hal A Lewis, Nazia Ahmed, Nicolas Szapiel, John A Newitt, Eric T Baldwin, Hong Xiao, Carol M Krause, Hyunsoo Park, Michelle Nophsker, Jonathan S Lippy, Catherine R Burton, David R Langley, John E Macor, Gene M Dubowchik
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 25 Issue 9 Pg. 1856-63 (May 01 2015) ISSN: 1464-3405 [Electronic] England
• PMID: 25845281 (Publication Type: Journal Article)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Aminopyridines
• Protein Kinase Inhibitors
• Pyridones
• Pyrroles
• Glycogen Synthase Kinase 3

Topics

• Aminopyridines (administration & dosage, chemistry, pharmacology)
• Animals
• Crystallography, X-Ray
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Discovery
• Glycogen Synthase Kinase 3 (antagonists & inhibitors, metabolism)
• Humans
• Mice
• Mice, Transgenic
• Models, Molecular
• Molecular Structure
• Protein Kinase Inhibitors (administration & dosage, chemistry, pharmacology)
• Pyridones (chemistry)
• Pyrroles (chemistry)
• Structure-Activity Relationship