R75251, A NEW INHIBITOR OF STEROID-BIOSYNTHESIS

R 75251, a new imidazole derivative, inhibited the conversion of androgens to estrogens, of progestins to androstenedione and testosterone, and of 11‐deoxycorticosterone to corti‐costerone in human placenta microsomes, subcellular fraction of rat testis, bovine adreno‐cortical mitochondria, in cultured rat granulosa, testicular and adrenal cells, respectively. In vitro, no effect on cholesterol synthesis and cholesterol side‐chain cleavage was found at concentrations up to 10 μM. In rat granulosa cells, no effect on progesterone production was detected. In vitro, no effect on steroid radioligand binding was observed. In male volunteers, a single dose of 300 mg of R 75251 significantly lowered plasma testosterone and estradiol for 24 hours and increased plasma concentration of 17α‐hydroxy‐progesterone and progesterone. As compared with ketoconazole high dose (600 mg b.i.d), R 75251 (300 mg b.i.d) was at least as efficacious as inhibitor of testosterone synthesis when studied during ACTH stimulation. In contrast to ketoconazole, R 75251 did not significantly affect circulating adrenal androgen levels in male volunteers. Precursors of gluco‐ and mineralocorticoids such as 11‐deoxycortisol and 11‐deoxycorticosterone accumulated more than after ketoconazole administration. The data show that the cytochrome P450‐dependent aromatase, 17‐hydroxylase/17,20‐lyase, and 11‐hydroxylase are the target enzymes for R 75251. Copyright © 1990 Wiley‐Liss, Inc., A Wiley Company