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Design and synthesis of substituted imidazole and triazole N-phenylbenzo[d]oxazolamine inhibitors of retinoic acid metabolizing enzyme CYP26

Research output: Contribution to journalJournal article

Published

  • Stephane Pautus
  • Ahmed S. Aboraia
  • Claire E. Bassett
  • Andrea Brancale
  • Michael Coogan
  • Claire Simons
Journal publication date2009
JournalJournal of Enzyme Inhibition and Medicinal Chemistry
Journal number2
Volume24
Number of pages12
Pages487-498
Original languageEnglish

Abstract

The design of N-phenylbenzo[d]oxazolamines as CYP26A1 inhibitors involved ligand docking experiments using molecular modeling (FlexX) and analysis of ligand interactions at the binding domain. The synthesis of the benzooxazol-2-yl-[phenyl-imidazol-1-yl-methyl)phenyl]amines was achieved by cyclisation of the corresponding isothiocyanates with subsequent introduction of the haem-binding heterocycle. Triazole and tetrazole derivatives were also prepared for comparison with the lead imidazole derivative. The benzooxazol-2-yl-[phenyl-imidazol-1-yl-methyl)phenyl]amines with small substituents in the phenyl ring were moderately potent CYP26A1 inhibitors (IC50 8 and 12 μM) and comparable with liarozole (IC50 7 μM).