title: 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-14C(U)]BMS-770767 was synthesized in two steps from a late-stage intermediate and [14C(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-14C(U)]BMS-770767. The radiochemical purity of the synthesized [phenyl-14C(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, [13C6]BMT-770767 was prepared in two steps from a late-stage intermediate and [13C6]2-chlorophenol.
authors.affiliation: Bristol-Myers Squibb Research and Development, Discovery Chemistry Platforms-Radiochemistry, Route 206 and Province Line Road, Princeton, NJ, 08540, USA.
authors.forename: Brad D
authors.initials: BD
authors.lastname: Maxwell
authors.affiliation: Bristol-Myers Squibb Research and Development, Discovery Chemistry Platforms-Radiochemistry, Route 206 and Province Line Road, Princeton, NJ, 08540, USA.
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Bonacorsi
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors; D065966:Absorption, Physicochemical; D001711:Biotransformation; D002250:Carbon Radioisotopes / Q000737:chemistry*; D060326:Chemistry Techniques, Synthetic; D004791:Enzyme Inhibitors / Q000032:analysis* / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D011725:Pyridines / Q000032:analysis* / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011854:Radiochemistry; D014230:Triazoles / Q000032:analysis* / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology
chemical_list: C000625006:BMS-770767; D002250:Carbon Radioisotopes; D004791:Enzyme Inhibitors; D011725:Pyridines; D014230:Triazoles; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1
keywords: 11β-HSD1; carbon-14; human ADME; stable isotope-labelled synthesis; type 2 diabetes