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

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

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.

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