Synthesis and optimization of picolinamide derivatives as a novel class of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors.

The synthesis and structure-activity relationship of a series of 6-substituted picolinamide inhibitors of 11β-hydroxysteroid dehydrogenase type 1 are described. The optimization of the left-hand side of lead compound 1 resulted in the discovery of the highly potent, selective, and orally available inhibitor 24, which demonstrated an excellent activity in a mouse ex vivo pharmacodynamic model. Moreover, compound 24 reduced the blood glucose and improved the lipid profiles in ob/ob mice after oral administration.