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

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

doi:10.1016/j.bmcl.2015.03.046

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

Bioorg Med Chem Lett. 2015 May 1;25(9):1856-63. doi: 10.1016/j.bmcl.2015.03.046. Epub 2015 Mar 24.

Authors

Prasanna Sivaprakasam¹, Xiaojun Han², Rita L Civiello³, Swanee Jacutin-Porte³, Kevin Kish⁴, Matt Pokross⁴, Hal A Lewis⁴, Nazia Ahmed⁴, Nicolas Szapiel⁴, John A Newitt⁴, Eric T Baldwin⁴, Hong Xiao³, Carol M Krause³, Hyunsoo Park³, Michelle Nophsker³, Jonathan S Lippy⁴, Catherine R Burton³, David R Langley³, John E Macor³, Gene M Dubowchik³

Affiliations

¹ Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA. Electronic address: prasanna.siva@bms.com.
² Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA. Electronic address: xiaojun.han@bms.com.
³ Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
⁴ Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543, USA.

PMID: 25845281
DOI: 10.1016/j.bmcl.2015.03.046

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.

Keywords: Alzheimer’s disease; GSK-3; Kinase; Pyrrolopyridinone; Tau-phosphorylation.

MeSH terms

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

Substances

Aminopyridines
Protein Kinase Inhibitors
Pyridones
Pyrroles
Glycogen Synthase Kinase 3