Discovery of a N'-hydroxyphenylformamidine derivative HET0016 as a potent and selective 20-HETE synthase inhibitor

Bioorg Med Chem Lett. 2001 Dec 3;11(23):2993-5. doi: 10.1016/s0960-894x(01)00614-x.

Abstract

N-(4-Butyl-2-methylphenyl)-N'-hydroxyformamidine (HET0016) was evaluated as the first potent and selective inhibitor of 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE) synthase. The IC(50) value of HET0016 for the production of 20-HETE from arachidonic acid (AA) by human renal microsomes was 8.9+/-2.7 nM, with over 200 times the selectivity of xenobiotic-metabolizing cytochrome P450 enzymes. An examination of the structure-activity relationship revealed that the unsubstituted hydroxyformamidine moiety and the substituent at the para-position of the N-hydroxyformamidine moiety are necessary for the potent activity of HET0016.

MeSH terms

  • Amidines / chemistry
  • Amidines / pharmacology*
  • Cytochrome P-450 CYP2D6 / metabolism
  • Cytochrome P-450 CYP2D6 Inhibitors
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Hydroxyeicosatetraenoic Acids / metabolism
  • Inhibitory Concentration 50
  • Kidney / drug effects
  • Kidney / metabolism
  • Microsomes / drug effects
  • Microsomes / metabolism
  • Structure-Activity Relationship

Substances

  • Amidines
  • Cytochrome P-450 CYP2D6 Inhibitors
  • Enzyme Inhibitors
  • HET0016
  • Hydroxyeicosatetraenoic Acids
  • 20-hydroxy-5,8,11,14-eicosatetraenoic acid
  • Cytochrome P-450 CYP2D6