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.
Prasanna Sivaprakasam  1 ,  Xiaojun Han  2 ,  Rita L Civiello  3 ,  Swanee Jacutin-Porte  3 ,  Kevin Kish  4 ,  Matt Pokross  4 ,  Hal A Lewis  4 ,  Nazia Ahmed  4 ,  Nicolas Szapiel  4 ,  John A Newitt  4 ,  Eric T Baldwin  4 ,  Hong Xiao  3 ,  Carol M Krause  3 ,  Hyunsoo Park  3 ,  Michelle Nophsker  3 ,  Jonathan S Lippy  4 ,  Catherine R Burton  3 ,  David R Langley  3 ,  John E Macor  3 ,  Gene M Dubowchik  3
Affiliations
  • 1. Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA. Electronic address: [email protected].
  • 2. Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA. Electronic address: [email protected].
  • 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.
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