Structure–activity relationship (SAR) studies on substituted N-(pyridin-3-yl)-2-amino-isonicotinamides as highly potent and selective glycogen synthase kinase-3 (GSK-3) inhibitors. (1st February 2023)

• Record Type: Journal Article
• Authors: Luo, Guanglin; Chen, Ling; Jacutin-Porte, Swanee; Han, Ying; Burton, Catherine R.; Xiao, Hong; Krause, Carol M.; Cao, Yang; Liu, Nengyin; Kish, Kevin; Lewis, Hal A.; Macor, John E.; Dubowchik, Gene M.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 81(2023)
• Publication Date: 2023-02-01
• Subjects: GSK-3 inhibitor -- Isonicotinamide -- SAR studies -- Alzheimer's disease; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2023.129143
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: In our continuing efforts to explore structure–activity relationships around the novel class of potent, isonicotinamide-based GSK3 inhibitors described in our previous report, we extensively explored structural variations around both 4/5-pyridine substitutions and the amide group. Some analogs were found to have greatly improved pTau lowering potency while retaining high kinase selectivity. In contrast to previous active compounds 1a-c, a close analog 3h did not show in vivo efficacy in a triple-transgenic mouse Alzheimer's disease model. In general, these 2‑pyridinyl amide derivatives were prone to amidase mediated hydrolysis in mouse plasma.