Synthesis, in Vitro Covalent Binding Evaluation, and Metabolism of 14C-Labeled Inhibitors of 11β-HSD1

In this letter, we reported the design and synthesis of three potent, selective, and orally bioavailable 11 beta-HSD1 inhibitors labeled with C-14: AMG 456 (<bold>1</bold>), AM-6949 (<bold>2</bold>), and AM-7715 (<bold>3</bold>). We evaluated the covalent protein binding of the labeled inhibitors in human liver microsomes in vitro and assessed their potential bioactivation risk in humans. We then studied the in vitro mechanism of <bold>2</bold> in human hepatocytes and the formation of reactive intermediates. Our study results suggest that <bold>1</bold> and <bold>3</bold> have low potential for metabolic bioactivation in humans, while <bold>2</bold> has relatively high risk.