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

Journal Article · · Journal of Medicinal Chemistry
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  1. Bristol-Myers Squibb Research & Development, Wallingford, CT (United States)
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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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE
OSTI ID:
1352262
Journal Information:
Journal of Medicinal Chemistry, Vol. 59, Issue 3; ISSN 0022-2623
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 46 works
Citation information provided by
Web of Science

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Cited By (7)

Glycogen synthase kinase 3 (GSK-3) inhibitors: a patent update (2014-2015) journal November 2016
Identification of dual kinase inhibitors of CK2 and GSK3β: combined qualitative and quantitative pharmacophore modeling approach text January 2017
The selective GSK3 inhibitor, SAR502250, displays neuroprotective activity and attenuates behavioral impairments in models of neuropsychiatric symptoms of Alzheimer’s disease in rodents journal December 2019
Identification of dual kinase inhibitors of CK2 and GSK3β: combined qualitative and quantitative pharmacophore modeling approach journal January 2017
A network pharmacology study on the triterpene saponins from Medicago sativa L. for the treatment of Neurodegenerative diseases journal June 2019
Receptor-based pharmacophore modeling, virtual screening, and molecular docking studies for the discovery of novel GSK-3β inhibitors journal May 2019
Identification of dual kinase inhibitors of CK2 and GSK3β: combined qualitative and quantitative pharmacophore modeling approach text January 2017

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60 APPLIED LIFE SCIENCES
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anions
peptides and proteins