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

Abstract

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- C(U)]BMS-770767 was synthesized in two steps from a late-stage intermediate and [ 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- C(U)]BMS-770767. The radiochemical purity of the synthesized [phenyl- 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, [ C ]BMT-770767 was prepared in two steps from a late-stage intermediate and [ C ]2-chlorophenol.

The syntheses of [13C6] and [phenyl‐14C(U)]BMS‐816336, an inhibitor of 11β‐hydroxysteroid dehydrogenase type 1, for type 2 diabetes

“…To further the development of BMS‐816336, it was necessary to prepare [phenyl‐ 14 C(U)]BMS‐816336 for metabolic profiling and stable‐isotope labeled BMS‐816336 for use as a liquid chromatography/mass spectrometry (LC/MS) standard. Radiolabeled and stable‐isotope labeled BMS‐816336 represent the third in a series of labeled Bristol‐Myers Squibb assets in the 11β‐HSD1 inhibitor class of compounds …”

“…Radiolabeled and stable-isotope labeled BMS-816336 represent the third in a series of labeled Bristol-Myers Squibb assets in the 11β-HSD1 inhibitor class of compounds. 10,11 2 | EXPERIMENTAL…”