Design, Structure-Activity Relationships, and In Vivo Evaluation of Potent and Brain-Penetrant Imidazo[1,2-b]pyridazines as Glycogen Synthase Kinase-3β (GSK-3β) Inhibitors.

Abstract

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that regulates numerous cellular processes, including metabolism, proliferation, and cell survival. Due to its multifaceted role, GSK-3 has been implicated in a variety of diseases, including Alzheimer's disease, type 2 diabetes, cancer, and mood disorders. GSK-3β has been linked to the formation of the neurofibrillary tangles associated with Alzheimer's disease that arise from the hyperphosphorylation of tau protein. The design and synthesis of a series of imidazo[1,2-b]pyridazine derivatives that were evaluated as GSK-3β inhibitors are described herein. Structure-activity relationship studies led to the identification of potent GSK-3β inhibitors. In vivo studies with 47 in a triple-transgenic mouse Alzheimer's disease model showed that this compound is a brain-penetrant, orally bioavailable GSK-3β inhibitor that significantly lowered levels of phosphorylated tau.

• Authors: Richard A Hartz, Vijay T Ahuja, Prasanna Sivaprakasam, Hong Xiao, Carol M Krause, Wendy J Clarke, Kevin Kish, Hal Lewis, Nicolas Szapiel, Ramu Ravirala, Sayali Mutalik, Deepa Nakmode, Devang Shah, Catherine R Burton, John E Macor, Gene M Dubowchik
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 66 Issue 6 Pg. 4231-4252 (03 23 2023) ISSN: 1520-4804 [Electronic] United States
• PMID: 36950863 (Publication Type: Journal Article)

Chemical References

• Glycogen Synthase Kinase 3 beta
• Glycogen Synthase Kinase 3
• tau Proteins

Topics

• Mice
• Animals
• Alzheimer Disease (metabolism)
• Glycogen Synthase Kinase 3 beta (metabolism)
• Glycogen Synthase Kinase 3 (metabolism)
• Diabetes Mellitus, Type 2
• tau Proteins (metabolism)
• Mice, Transgenic
• Brain (metabolism)
• Structure-Activity Relationship
• Phosphorylation