Design, synthesis, and biological activity of substituted 2-amino-5-oxo-5H-chromeno[2,3-b]pyridine-3-carboxylic acid derivatives as inhibitors of the inflammatory kinases TBK1 and IKKε for the treatment of obesity.

Abstract

The non-canonical IκB kinases TANK-binding kinase 1 (TBK1) and inhibitor of nuclear factor kappa-B kinase ε (IKKε) play a key role in insulin-independent pathways that promote energy storage and block adaptive energy expenditure during obesity. Utilizing docking calculations and the x-ray structure of TBK1 bound to amlexanox, an inhibitor of these kinases with modest potency, a series of analogues was synthesized to develop a structure activity relationship (SAR) around the A- and C-rings of the core scaffold. A strategy was developed wherein R7 and R8 A-ring substituents were incorporated late in the synthetic sequence by utilizing palladium-catalyzed cross-coupling reactions on appropriate bromo precursors. Analogues display IC50 values as low as 210 nM and reveal A-ring substituents that enhance selectivity toward either kinase. In cell assays, selected analogues display enhanced phosphorylation of p38 or TBK1 and elicited IL-6 secretion in 3T3-L1 adipocytes better than amlexanox. An analogue bearing a R7 cyclohexyl modification demonstrated robust IL-6 production in 3T3-L1 cells as well as a phosphorylation marker of efficacy and was tested in obese mice where it promoted serum IL-6 response, weight loss, and insulin sensitizing effects comparable to amlexanox. These studies provide impetus to expand the SAR around the amlexanox core toward uncovering analogues with development potential.

• Authors: Tyler S Beyett, Xinmin Gan, Shannon M Reilly, Andrew V Gomez, Louise Chang, John J G Tesmer, Alan R Saltiel, Hollis D Showalter
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 26 Issue 20 Pg. 5443-5461 (11 01 2018) ISSN: 1464-3391 [Electronic] England
• PMID: 30270002 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

• Anti-Obesity Agents
• Chromans
• Protein Kinase Inhibitors
• Pyridines
• Protein Serine-Threonine Kinases
• TBK1 protein, human
• I-kappa B Kinase
• IKBKE protein, human

Topics

• 3T3-L1 Cells
• Amination
• Animals
• Anti-Obesity Agents (chemical synthesis, chemistry, pharmacology, therapeutic use)
• Chromans (chemical synthesis, chemistry, pharmacology, therapeutic use)
• Crystallography, X-Ray
• Drug Design
• Humans
• I-kappa B Kinase (antagonists & inhibitors, metabolism)
• Mice
• Molecular Docking Simulation
• Obesity (drug therapy, metabolism)
• Protein Kinase Inhibitors (chemical synthesis, chemistry, pharmacology, therapeutic use)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Pyridines (chemical synthesis, chemistry, pharmacology, therapeutic use)