生物活性

• 描述11β-HSD1 (11β-hydroxysteroid dehydrogenase type 1), a member of the short chain dehydrogenase/reductase (SDR) superfamily, is responsible for the local conversion of inactive cortisone to the active glucocorticoid cortisol. It is proposed to be critical for the development of metabolic syndrome. BI 135585 is a potent and selective 11β-HSD1 inhibitor with an average IC50 of 13nM. It inhibited cellular 11β-HSD1 activity in human preadipocytes with average IC50 value of 1nM. Inhibition of 11β-HSD1 in human adipose tissue ex vivo inhibited the conversion of cortisone to cortisol with an average IC50 value 11nM. Inhibition of the conversion of cortisone to cortisol by BI 135585 in an ex vivo tissue assay showed that BI 135585 inhibited 56% and 83% of enzyme activity at 1mg/kg and 3mg/kg in perirenal adipose tissue, inhibited 67% and 95% of enzyme activity in abdominal subcutaneous adipose tissue, inhibited 75% and 92% of liver 11β-HSD1 enzyme activity, respectively, at 7h post treatment. Also it inhibited 70% and 77% in perirenal and abdominal SC adipose at dose of 10mg/kg after 20h. BI-135585 exhibited > 1000x selectivity over 11β-HSD2, 3β-hydroxysteroid dehydrogenase type 2 (3β-HSD2), 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) and pregnane X receptor (PXR). When administered intravenously to cynomolgus monkeys, BI-135585 showed low clearance rates and good exposure, the longest MRT, but did not inhibit hERG.
• 作用机制BI 135585 binds in the substrate binding pocket of the active site of 11β-HSD1.