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Title: Discovery of Isonicotinamides as Highly Selective, Brain Penetrable, and Orally Active Glycogen Synthase Kinase-3 Inhibitors

Abstract

GSK-3 is a serine/threonine kinase that has numerous substrates. Many of these proteins are involved in the regulation of diverse cellular functions, including metabolism, differentiation, proliferation, and apoptosis. Inhibition of GSK-3 may be useful in treating a number of diseases including Alzheimer’s disease (AD), type II diabetes, mood disorders, and some cancers, but the approach poses significant challenges. Here, we present a class of isonicotinamides that are potent, highly kinase-selective GSK-3 inhibitors, the members of which demonstrated oral activity in a triple-transgenic mouse model of AD. Here, the remarkably high kinase selectivity and straightforward synthesis of these compounds bode well for their further exploration as tool compounds and therapeutics.

Authors:
 [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1]
+ Show Author Affiliations
  1. Bristol-Myers Squibb Research & Development, Wallingford, CT (United States)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1352262
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 59; Journal Issue: 3; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; rodent models; inhibitors; inhibition; anions; peptides and proteins

Citation Formats

Luo, Guanglin, Chen, Ling, Burton, Catherine R., Xiao, Hong, Sivaprakasam, Prasanna, Krause, Carol M., Cao, Yang, Liu, Nengyin, Lippy, Jonathan, Clarke, Wendy J., Snow, Kimberly, Raybon, Joseph, Arora, Vinod, Pokross, Matt, Kish, Kevin, Lewis, Hal A., Langley, David R., Macor, John E., and Dubowchik, Gene M. Discovery of Isonicotinamides as Highly Selective, Brain Penetrable, and Orally Active Glycogen Synthase Kinase-3 Inhibitors. United States: N. p., 2016. Web. doi:10.1021/acs.jmedchem.5b01550.
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Luo, Guanglin, Chen, Ling, Burton, Catherine R., Xiao, Hong, Sivaprakasam, Prasanna, Krause, Carol M., Cao, Yang, Liu, Nengyin, Lippy, Jonathan, Clarke, Wendy J., Snow, Kimberly, Raybon, Joseph, Arora, Vinod, Pokross, Matt, Kish, Kevin, Lewis, Hal A., Langley, David R., Macor, John E., & Dubowchik, Gene M. Discovery of Isonicotinamides as Highly Selective, Brain Penetrable, and Orally Active Glycogen Synthase Kinase-3 Inhibitors. United States. https://doi.org/10.1021/acs.jmedchem.5b01550
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Luo, Guanglin, Chen, Ling, Burton, Catherine R., Xiao, Hong, Sivaprakasam, Prasanna, Krause, Carol M., Cao, Yang, Liu, Nengyin, Lippy, Jonathan, Clarke, Wendy J., Snow, Kimberly, Raybon, Joseph, Arora, Vinod, Pokross, Matt, Kish, Kevin, Lewis, Hal A., Langley, David R., Macor, John E., and Dubowchik, Gene M. Mon . "Discovery of Isonicotinamides as Highly Selective, Brain Penetrable, and Orally Active Glycogen Synthase Kinase-3 Inhibitors". United States. https://doi.org/10.1021/acs.jmedchem.5b01550. https://www.osti.gov/servlets/purl/1352262.
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@article{osti_1352262,
title = {Discovery of Isonicotinamides as Highly Selective, Brain Penetrable, and Orally Active Glycogen Synthase Kinase-3 Inhibitors},
author = {Luo, Guanglin and Chen, Ling and Burton, Catherine R. and Xiao, Hong and Sivaprakasam, Prasanna and Krause, Carol M. and Cao, Yang and Liu, Nengyin and Lippy, Jonathan and Clarke, Wendy J. and Snow, Kimberly and Raybon, Joseph and Arora, Vinod and Pokross, Matt and Kish, Kevin and Lewis, Hal A. and Langley, David R. and Macor, John E. and Dubowchik, Gene M.},
abstractNote = {GSK-3 is a serine/threonine kinase that has numerous substrates. Many of these proteins are involved in the regulation of diverse cellular functions, including metabolism, differentiation, proliferation, and apoptosis. Inhibition of GSK-3 may be useful in treating a number of diseases including Alzheimer’s disease (AD), type II diabetes, mood disorders, and some cancers, but the approach poses significant challenges. Here, we present a class of isonicotinamides that are potent, highly kinase-selective GSK-3 inhibitors, the members of which demonstrated oral activity in a triple-transgenic mouse model of AD. Here, the remarkably high kinase selectivity and straightforward synthesis of these compounds bode well for their further exploration as tool compounds and therapeutics.},
doi = {10.1021/acs.jmedchem.5b01550},
journal = {Journal of Medicinal Chemistry},
number = 3,
volume = 59,
place = {United States},
year = {Mon Jan 11 00:00:00 EST 2016},
month = {Mon Jan 11 00:00:00 EST 2016}
}
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https://doi.org/10.1021/acs.jmedchem.5b01550
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