R 75251, a new inhibitor of steroid biosynthesis

Area of Science:

• Endocrinology
• Biochemistry
• Pharmacology

Background:

• Steroidogenesis involves complex enzymatic pathways crucial for hormone production.
• Inhibitors of steroidogenic enzymes are vital for treating hormone-dependent conditions.
• Cytochrome P450 enzymes play critical roles in synthesizing androgens, estrogens, progestins, and corticosteroids.

Purpose of the Study:

• To investigate the inhibitory effects of R 75251 on key steroidogenic enzymes.
• To evaluate the in vitro and in vivo efficacy of R 75251 as a steroidogenesis inhibitor.
• To compare the effects of R 75251 with ketoconazole in male volunteers.

Main Methods:

• In vitro enzyme inhibition assays using human placenta microsomes, rat testis fractions, and bovine adrenocortical mitochondria.
• Cell-based assays with cultured rat granulosa, testicular, and adrenal cells.
• In vivo study in male volunteers administering a single dose of R 75251 and comparing with ketoconazole during ACTH stimulation.

Main Results:

• R 75251 inhibited androgen to estrogen conversion, progestin to androstenedione/testosterone conversion, and 11-deoxycorticosterone to corticosterone conversion.
• In vitro studies showed no effect on cholesterol synthesis, side-chain cleavage, progesterone production, or steroid radioligand binding at tested concentrations.
• In male volunteers, R 75251 significantly lowered plasma testosterone and estradiol, while increasing 17 alpha-hydroxyprogesterone and progesterone. It demonstrated comparable efficacy to high-dose ketoconazole in inhibiting testosterone synthesis but did not affect adrenal androgens.
• Accumulation of gluco- and mineralocorticoid precursors (11-deoxycortisol, 11-deoxycorticosterone) was observed after R 75251 administration.

Conclusions:

• R 75251 is a potent inhibitor of cytochrome P450-dependent aromatase, 17-hydroxylase/17,20-lyase, and 11-hydroxylase.
• The compound demonstrates significant in vivo efficacy in suppressing key steroidogenic pathways.
• R 75251 exhibits a distinct inhibitory profile compared to ketoconazole, particularly regarding adrenal androgen levels.