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

Bioorg Med Chem Lett. 2015 Apr 15;25(8):1679-1683. doi: 10.1016/j.bmcl.2015.03.003. Epub 2015 Mar 10.

Abstract

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.

Keywords: 11β-HSD1 inhibitor; Diabetes; Hyperlipidemia; Metabolic syndrome; Picolinamide.

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism*
  • Administration, Oral
  • Amides / chemistry
  • Amides / pharmacokinetics
  • Amides / therapeutic use
  • Animals
  • Blood Glucose / analysis
  • Catalysis
  • Diabetes Mellitus, Experimental / drug therapy
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / therapeutic use
  • HEK293 Cells
  • Half-Life
  • Humans
  • Lipids / blood
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Palladium / chemistry
  • Picolinic Acids / chemistry*
  • Picolinic Acids / pharmacokinetics
  • Picolinic Acids / therapeutic use
  • Protein Binding
  • Structure-Activity Relationship

Substances

  • Amides
  • Blood Glucose
  • Enzyme Inhibitors
  • Lipids
  • Picolinic Acids
  • Palladium
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1
  • picolinamide