Discovery of a Potent, Selective, and Orally Bioavailable Acidic 11尾-Hydroxysteroid Dehydrogenase Type 1 (11尾-HSD1) Inhibitor: Discovery of 2-[(3S)-1-[5-(Cyclohexylcarbamoyl)-6-propylsulfanylpy
文摘
Inhibition of 11尾-HSD1 is an attractive mechanism for the treatment of obesity and other elements of the metabolic syndrome. We report here the discovery of a nicotinic amide derived carboxylic acid class of inhibitors that has good potency, selectivity, and pharmacokinetic characteristics. Compound 11i (AZD4017) is an effective inhibitor of 11尾-HSD1 in human adipocytes and exhibits good druglike properties and as a consequence was selected for clinical development.