title: R 76713 and enantiomers: selective, nonsteroidal inhibitors of the cytochrome P450-dependent oestrogen synthesis.
abstract: The triazole derivative, R 76713 and its enantiomers R 83839(-) and R 83842(+) are effective inhibitors of the aromatization of androstenedione. For human placental microsomes, the (+) enantiomer (R 83824) is about 1.9- and 32-times more active than the racemate (IC50 2.6 nM) and the (-) enantiomer, respectively. R 83842 is about 30- and 1029-times more active than 4-hydroxyandrostene-3,17-dione and aminoglutethimide. This potency might originate from its high affinity for the microsomal cytochrome P450 (P450). Indeed, R 83842, compared to R 76713 and R 83839, forms a more stable P450-drug complex. Difference spectral measurements indicate that the triazole nitrogen N-4 coordinates to the haem iron. The reversed type 1 spectral changes suggest that R 76713 is able to displace the substrate from its binding place and the stable complex formed in particular with the (+) enantiomer suggests that its N-1-substituent occupies a lipophilic region of the apoprotein moiety. Kinetic analysis implies that there is a competitive part in the inhibition of the human placental aromatase by R 76713. The Ki values for R 76713, R 83842 and R 83839 are 1.3 nM, 0.7 nM and 18 nM, respectively. These results are indicative of stereospecificity for binding. Up to 10 microM, R 76713 and its enantiomers have no statistically significant effect on the regio- and stereoselective oxidations of testosterone in male rat liver microsomes. All three compounds have no effect on the P450-dependent cholesterol synthesis, cholesterol side-chain cleavage and 7 alpha-hydroxylation and 21-hydroxylase. At 10 microM, R 76713 has a slight effect on the bovine adrenal 11 beta-hydroxylase. This effect originates mainly from R 83839, the less potent aromatase inhibitor. On the other hand, the inhibition of the 17,20-lyase of rat testis observed at concentrations greater than or equal to 0.5 microM, originates rather from R 83842. However, 50% inhibition is only achieved at 1.8 microM R 83842, i.e. at a concentration about 1300-times higher than that needed to reach 50% inhibition of the human placental aromatase.
authors.affiliation: Janssen Research Foundation, Beerse, Belgium.
authors.forename: H
authors.initials: H
authors.lastname: Vanden Bossche
authors.forename: G
authors.initials: G
authors.lastname: Willemsens
authors.forename: I
authors.initials: I
authors.lastname: Roels
authors.forename: D
authors.initials: D
authors.lastname: Bellens
authors.forename: H
authors.initials: H
authors.lastname: Moereels
authors.forename: M C
authors.initials: MC
authors.lastname: Coene
authors.forename: L
authors.initials: L
authors.lastname: Le Jeune
authors.forename: W
authors.initials: W
authors.lastname: Lauwers
authors.forename: P A
authors.initials: PA
authors.lastname: Janssen
mesh_terms: D000311:Adrenal Glands / Q000187:drug effects; D000728:Androgens / Q000096:biosynthesis; D000735:Androstenedione / Q000494:pharmacology; D000818:Animals; D047072:Aromatase Inhibitors; D002417:Cattle; D065607:Cytochrome P-450 Enzyme Inhibitors; D004967:Estrogens / Q000096:biosynthesis*; D005260:Female; D008297:Male; D008861:Microsomes / Q000187:drug effects; D010920:Placenta / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D013053:Spectrophotometry; D013237:Stereoisomerism; D013552:Swine; D013737:Testis / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D000728:Androgens; D047072:Aromatase Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004967:Estrogens; D014230:Triazoles; C060523:vorozole; D000735:Androstenedione