Dual aromatase-steroid sulfatase inhibitors

J Med Chem. 2007 Jul 26;50(15):3540-60. doi: 10.1021/jm061462b. Epub 2007 Jun 20.

Abstract

By introducting the steroid sulfatase inhibitory pharmacophore into aromatase inhibitor 1 (YM511), two series of single agent dual aromatase-sulfatase inhibitors (DASIs) were generated. The best DASIs in vitro (JEG-3 cells) are 5, (IC50(aromatase) = 0.82 nM; IC50(sulfatase) = 39 nM), and 14, (IC50(aromatase) = 0.77 nM; IC50(sulfatase) = 590 nM). X-ray crystallography of 5, and docking studies of selected compounds into an aromatase homology model and the steroid sulfatase crystal structure are presented. Both 5 and 14 inhibit aromatase and sulfatase in PMSG pretreated adult female Wistar rats potently 3 h after a single oral 10 mg/kg dose. Almost complete dual inhibition is observed for 5 but the levels were reduced to 85% (aromatase) and 72% (sulfatase) after 24 h. DASI 5 did not inhibit aldosterone synthesis. The development of a potent and selective DASI should allow the therapeutic potential of dual aromatase-sulfatase inhibition in hormone-dependent breast cancer to be assessed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aromatase Inhibitors / chemical synthesis*
  • Aromatase Inhibitors / chemistry
  • Aromatase Inhibitors / pharmacology
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • Female
  • Humans
  • Models, Molecular*
  • Protein Conformation
  • Rats
  • Rats, Wistar
  • Steryl-Sulfatase / antagonists & inhibitors*
  • Steryl-Sulfatase / chemistry
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology
  • Triazoles / chemical synthesis*
  • Triazoles / chemistry
  • Triazoles / pharmacology

Substances

  • Aromatase Inhibitors
  • Sulfonamides
  • Triazoles
  • sulfamic acid 2-bromo-4-(((4-cyanophenyl)(1,2,4)triazol-4-ylamino)methyl)phenyl ester
  • sulfamic acid 5-(((4-cyanophenyl)(1,2,4)triazol-4-ylamino)methyl)-2-fluorophenyl ester
  • Steryl-Sulfatase