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
  • 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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