The synthesis and analysis of [phenyl-14 C(U)]BMS-770767 and [13 C6 ]BMS-770767 for use in discovery biotransformation, human ADME and bioanalytical studies

Type 2 diabetes is a significant worldwide health problem. To support the development of BMS-770767 as an inhibitor of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) for type 2 diabetes was required the synthesis of carbon-14-labelled material for use in metabolic profiling and for the human adsorption, distribution, metabolism and excretion (ADME) study. Initially, [phenyl-¹⁴ C(U)]BMS-770767 was synthesized in two steps from a late-stage intermediate and [¹⁴ C(U)]2-chlorophenol to give the desired final product in 18% yield. Later, the synthesis was completed for the human ADME clinical study using a combination of the discovery and process chemistry routes under cGMP to prepare [phenyl-¹⁴ C(U)]BMS-770767. The radiochemical purity of the synthesized [phenyl-¹⁴ C(U)]BMS-770767 after dilution with unlabelled clinical grade BMS-770767 was 99.1% having a specific activity of 1.61 μCi/mg. In addition, to support the quantification of BMS-770767 in LC/MS analyses, [¹³ C₆ ]BMT-770767 was prepared in two steps from a late-stage intermediate and [¹³ C₆ ]2-chlorophenol.

11β-HSD1; carbon-14; human ADME; stable isotope-labelled synthesis; type 2 diabetes.