Novel imidazol-1-ylmethyl substituted 1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-ones as potent and selective CYP11B1 inhibitors for the treatment of Cushing's syndrome

J Med Chem. 2012 Jul 26;55(14):6629-33. doi: 10.1021/jm3003872. Epub 2012 Jul 12.

Abstract

CYP11B1 inhibition is a promising therapy for Cushing's syndrome. Starting from etomidate, references I and II, the title compounds were designed and synthesized. Cyclopropyl analogue 4 was identified as a CYP11B1 inhibitor more potent (IC(50) = 2.2 nM) than leads and more selective (SF = 11) than I and metyrapone. Since it also showed potent inhibition of rat CYP11B1 and good selectivity over human CYP17 and CYP19, it is a promising candidate for further development.

MeSH terms

  • Animals
  • Aromatase / metabolism
  • Cushing Syndrome / drug therapy*
  • Cytochrome P-450 CYP11B2 / antagonists & inhibitors
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Humans
  • Imidazoles / chemistry*
  • Inhibitory Concentration 50
  • Quinolones / chemical synthesis
  • Quinolones / chemistry*
  • Quinolones / pharmacology*
  • Quinolones / therapeutic use
  • Rats
  • Stereoisomerism
  • Steroid 11-beta-Hydroxylase / antagonists & inhibitors*
  • Steroid 17-alpha-Hydroxylase / antagonists & inhibitors
  • Substrate Specificity

Substances

  • Enzyme Inhibitors
  • Imidazoles
  • Quinolones
  • Aromatase
  • Steroid 17-alpha-Hydroxylase
  • Cytochrome P-450 CYP11B2
  • Steroid 11-beta-Hydroxylase