2. Academic Validation
  3. Discovery of 2-(Anilino)pyrimidine-4-carboxamides as Highly Potent, Selective, and Orally Active Glycogen Synthase Kinase-3 (GSK-3) Inhibitors

Discovery of 2-(Anilino)pyrimidine-4-carboxamides as Highly Potent, Selective, and Orally Active Glycogen Synthase Kinase-3 (GSK-3) Inhibitors

  • J Med Chem. 2023 Jun 8;66(11):7534-7552. doi: 10.1021/acs.jmedchem.3c00364.
Richard A Hartz,  Vijay T Ahuja,  Guanglin Luo,  Ling Chen,  Prasanna Sivaprakasam,  Hong Xiao,  Carol M Krause,  Wendy J Clarke,  Songmei Xu,  John S Tokarski,  Kevin Kish,  Hal Lewis,  Nicolas Szapiel,  Ramu Ravirala 1,  Sayali Mutalik 1,  Deepa Nakmode 1,  Devang Shah 1,  Catherine R Burton,  John E Macor,  Gene M Dubowchik
Affiliations

Affiliation

  • 1 Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Plot No. 2 & 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India.
PMID: 37235865 DOI: 10.1021/acs.jmedchem.3c00364
Abstract

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that serves as an important regulator of a broad range of cellular functions. It has been linked to Alzheimer's disease as well as various Other Diseases, including mood disorders, type 2 diabetes, and Cancer. There is considerable evidence indicating that GSK-3β in the central nervous system plays a role in the production of abnormal, hyperphosphorylated, microtubule-associated Tau Protein found in neurofibrillary tangles associated with Alzheimer's disease. A series of analogues containing a pyrimidine-based hinge-binding heterocycle was synthesized and evaluated, leading to the identification of highly potent GSK-3 inhibitors with excellent kinase selectivity. Further evaluation of 34 and 40 in vivo demonstrated that these compounds are orally bioavailable, brain-penetrant GSK-3 inhibitors that lowered levels of phosphorylated tau in a triple-transgenic mouse Alzheimer's disease model.

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