R 76713, a new specific non-steroidal aromatase inhibitor

J Steroid Biochem. 1989 Jun;32(6):781-8. doi: 10.1016/0022-4731(89)90453-6.

Abstract

The effects of R 76713, a new triazole derivative, on rat ovarian, testicular and adrenal steroidogenesis were investigated both in vitro and in vivo. In vitro R 76713 is a very potent inhibitor of the aromatase enzyme in rat granulosa cells, showing an IC50-value of 3.0 +/- 0.2 nM. The compound is about 1000 times more active than aminoglutethimide which shows an IC50-value of 3900 +/- 2800 nM in the same system. R 76713 is also a highly selective aromatase inhibitor. In cultures of ovarian, testicular and adrenal cells, formation of progesterone, androgens and glucocorticoids was only affected by drug concentrations higher than 1 microM. In vivo, single oral drug doses of 0.05 mg/kg lowered plasma estradiol levels of PMSG-primed female rats by more than 90%. An ED50-value of 0.005 mg/kg could be calculated. A single oral dose of 1 mg/kg suppressed plasma estradiol levels almost completely for 24 h. A dose of 0.1 mg/kg lowered plasma estradiol by more than 90% for 8 h. In vivo, R 76713 also showed a highly selective profile. In LHRH/ACTH-injected rats, plasma levels of testicular and adrenal steroids remained unchanged after administration of a drug dose of 20 mg/kg. R 76713 at drug concentrations of 10 microM, showed no interaction in vitro with estrogen-, progestin-, androgen- and glucocorticoid-receptors. Given orally at 20 mg/kg for 3 days the compound also showed no estrogen or androgen agonistic or antagonistic effects.

Publication types

  • Comparative Study

MeSH terms

  • Adrenal Glands / enzymology
  • Aminoglutethimide / pharmacology
  • Animals
  • Aromatase Inhibitors*
  • Cells, Cultured / drug effects
  • Dose-Response Relationship, Drug
  • Estradiol / blood
  • Female
  • Granulosa Cells / enzymology
  • Male
  • Rats
  • Rats, Inbred Strains
  • Receptors, Androgen / drug effects
  • Receptors, Estrogen / drug effects
  • Receptors, Glucocorticoid / drug effects
  • Receptors, Progesterone / drug effects
  • Testis / enzymology
  • Triazoles / administration & dosage
  • Triazoles / pharmacology*

Substances

  • Aromatase Inhibitors
  • Receptors, Androgen
  • Receptors, Estrogen
  • Receptors, Glucocorticoid
  • Receptors, Progesterone
  • Triazoles
  • Aminoglutethimide
  • vorozole
  • Estradiol