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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.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2023 Mar 23; Vol. 66 (6), pp. 4231-4252. Date of Electronic Publication: 2023 Mar 09. - Publication Year :
- 2023
-
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.
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 66
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 36950863
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.3c00133