Synthesis, biological evaluation and molecular modelling studies of methyleneimidazole substituted biaryls as inhibitors of human 17alpha-hydroxylase-17,20-lyase (CYP17). Part I: Heterocyclic modifications of the core structure

Bioorg Med Chem. 2008 Feb 15;16(4):1992-2010. doi: 10.1016/j.bmc.2007.10.094. Epub 2007 Nov 4.


Novel chemical entities were prepared via Suzuki and S(N) reaction as AC-ring substrate mimetics of CYP17. The synthesised compounds 1-31 were tested for activity using human CYP17 expressed in Escherichia coli. Promising compounds were tested for selectivity against hepatic CYP enzymes (3A4, 2D6, 1A2, 2C9, 2C19, 2B6). Two potent inhibitors (27, IC50 = 373 nM/28, IC50 = 953 nM) were further examined in rats regarding their effects on plasma testosterone levels and their pharmacokinetic properties. Compound 28 was similarly active as abiraterone and showed better pharmacokinetic properties (higher bioavailability, t(1/2) 9.5 h vs 1.6 h). Docking studies revealed two new binding modes different from the one of the substrates and steroidal inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Biological Availability
  • Enzyme Inhibitors / chemical synthesis
  • Heterocyclic Compounds / chemical synthesis
  • Heterocyclic Compounds / pharmacokinetics*
  • Heterocyclic Compounds / pharmacology
  • Humans
  • Imidazoles / chemical synthesis
  • Imidazoles / pharmacokinetics*
  • Imidazoles / pharmacology
  • Inhibitory Concentration 50
  • Liver / enzymology
  • Models, Molecular*
  • Polycyclic Aromatic Hydrocarbons / chemistry
  • Steroid 17-alpha-Hydroxylase / antagonists & inhibitors*
  • Testosterone / blood


  • Enzyme Inhibitors
  • Heterocyclic Compounds
  • Imidazoles
  • Polycyclic Aromatic Hydrocarbons
  • Testosterone
  • Steroid 17-alpha-Hydroxylase