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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.

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-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.
AuthorsBrad D Maxwell, Samuel J Bonacorsi Jr
JournalJournal of labelled compounds & radiopharmaceuticals (J Labelled Comp Radiopharm) Vol. 59 Issue 14 Pg. 657-664 (12 2016) ISSN: 1099-1344 [Electronic] England
PMID27460954 (Publication Type: Journal Article)
CopyrightCopyright © 2016 John Wiley & Sons, Ltd.
Chemical References
  • BMS-770767
  • Carbon Radioisotopes
  • Enzyme Inhibitors
  • Pyridines
  • Triazoles
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1
Topics
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 (antagonists & inhibitors)
  • Absorption, Physicochemical
  • Biotransformation
  • Carbon Radioisotopes (chemistry)
  • Chemistry Techniques, Synthetic
  • Enzyme Inhibitors (analysis, chemical synthesis, metabolism, pharmacology)
  • Humans
  • Pyridines (analysis, chemical synthesis, metabolism, pharmacology)
  • Radiochemistry
  • Triazoles (analysis, chemical synthesis, metabolism, pharmacology)

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