Inhibition of aromatase activity in the rat by aminoglutethimide and related compounds

Two compounds possessing aromatase inhibitory activity have been evaluated for their effects on oestradiol (E2) biosynthesis in the rat. These compounds, structurally related to aminoglutethimide (1), were administered intra-peritoneally at two dose levels to 10 week old female rats previously treated with pregnant mares' serum gonadotrophin (PMSG, 100 i.u. subcutaneously every other day for 9 days). Three hours after dosing, blood was collected and plasma oestradiol levels determined by RIA. Aminoglutethimide, 3-(4'-aminophenyl-3-ethylpyrrolidine-2,5-dione (2) and N-methyl-3-(4'-aminophenyl)-3-ethylpyrrolidine-2,5-dione (3) decreased E2 blood levels by 98, 97 and 82% of control levels respectively (n = 6) at a dose of 50 mg/kg. Similarly effective inhibition was also observed at a dose of 25 mg/kg (n = 4). Ovarian aromatase activity, assessed by incubating the homogenised ovaries of treated rats with tritium-labelled androstenedione (0.2 microM) or testosterone (1 microM), indicated that residual enzyme activity was reduced compared with controls. Aminoglutethimide, and the new pyrrolidinedione aromatase inhibitors 2 and 3, are therefore effective inhibitors of E2 biosynthesis in the rat with functioning ovarian activity.