6-Position optimization of tricyclic 4-quinolone-based inhibitors of glycogen synthase kinase-3β: Discovery of nitrile derivatives with picomolar potency

• Published in: Bioorganic & medicinal chemistry letters 2012-01, Vol.22 (2), p.1005-1008
• Main Authors: Li, Bei, Cociorva, Oana M., Nomanbhoy, Tyzoon, Li, Qiang, Nakamura, Kai, Nomura, Masahiro, Okada, Kyoko, Yumoto, Kazuhiro, Liyanage, Marek, Zhang, Melissa C., Aban, Arwin, Szardenings, Anna Katrin, Kozarich, John W., Kohno, Yasushi, Shreder, Kevin R.
• Format: Article
• Language: English
• Subjects: 4-Quinolone; 6-Nitrile; 6-Tetrazole; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; anti-infective properties; Biological and medical sciences; carboxylic acids; chemical derivatives; Dose-Response Relationship, Drug; enzyme inhibitors; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Escherichia coli - drug effects; glycogen (starch) synthase; Glycogen Synthase Kinase 3 - antagonists & inhibitors; Glycogen Synthase Kinase 3 beta; GSK-3β inhibitor; Kinase profiling; Medical sciences; Microbial Sensitivity Tests; Molecular Structure; nitriles; Nitriles - chemistry; Pharmacology. Drug treatments; Quinolizines - chemical synthesis; Quinolizines - chemistry; Quinolizines - pharmacology; quinolones; Staphylococcus aureus - drug effects; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.12.006

We previously disclosed tricylic, 6-carboxylic acid-bearing 4-quinolones as GSK-3β inhibitors. Herein we discuss the optimization of this series to yield a series of more potent 6-nitrile analogs with insignificant anti-microbial activity. Finally, kinase profiling indicated that members of this class were highly specific GSK-3 inhibitors.