Synthesis and biological evaluation of picolinamides as potent inhibitors of 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1)

摘要

Synthesis of a series of 6-substituted picolinamide derivatives and their inhibitory activities against 11b-hydroxysteroid dehydrogenase type 1 are described. Optimization of the initial hit compound, N-cyclohexyl-6-(piperidin-1-yl)picolinamide (1) from high throughput screening of in-house library resulted in the discovery of the highly potent and metabolically stable compound 25, which was efficacious in a mouse ex vivo pharmacodynamic model and reduced the fasting blood glucose and insulin levels in a HF/STZ mouse model after oral dosing. (C) 2014 Elsevier Ltd. All rights reserved.