R 76713, a new specific non-steroidal aromatase inhibitor.
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.
Department of Endocrinology and Oncology, Janssen Research Foundation, Beerse, Belgium.
W
W
Wouters
R
R
De Coster
M
M
Krekels
J
J
van Dun
D
D
Beerens
C
C
Haelterman
A
A
Raeymaekers
E
E
Freyne
J
J
Van Gelder
M
M
Venet
D000311:Adrenal Glands / Q000201:enzymology; D000616:Aminoglutethimide / Q000494:pharmacology; D000818:Animals; D047072:Aromatase Inhibitors; D002478:Cells, Cultured / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000097:blood; D005260:Female; D006107:Granulosa Cells / Q000201:enzymology; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011944:Receptors, Androgen / Q000187:drug effects; D011960:Receptors, Estrogen / Q000187:drug effects; D011965:Receptors, Glucocorticoid / Q000187:drug effects; D011980:Receptors, Progesterone / Q000187:drug effects; D013737:Testis / Q000201:enzymology; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology*
D047072:Aromatase Inhibitors; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D011965:Receptors, Glucocorticoid; D011980:Receptors, Progesterone; D014230:Triazoles; D000616:Aminoglutethimide; C060523:vorozole; D004958:Estradiol