Beyett, Tyler S.; Gan, Xinmin; Reilly, Shannon M.; Gomez, Andrew V.; Chang, Louise; Tesmer, John J. G.; Saltiel, Alan R.; Showalter, Hollis D. published the artcile< 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>, Application of C19H34O2, the main research area is aminooxochromenopyridinecarboxylate inhibitor inflammatory kinase antiobesity obesity; crystal structure; Amlexanox; Inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKKε); Obesity; SAR; TANK-binding kinase 1 (TBK1); TBK1·amlexanox co-crystal.
The noncanonical 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 analogs 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. Analogs display IC50 values as low as 210 nM and reveal A-ring substituents that enhance selectivity toward either kinase. In cell assays, selected analogs display enhanced phosphorylation of p38 or TBK1 and elicited IL-6 secretion in 3T3-L1 adipocytes better than amlexanox. An analog 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 analogs with development potential.
Bioorganic & Medicinal Chemistry published new progress about Antiobesity agents. 112-63-0 belongs to class esters-buliding-blocks, and the molecular formula is C19H34O2, Application of C19H34O2.
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