The New Aromatase Inhibitor CGS-16949A SuppressesAldosterone and Cortisol Production by Human Adrenal Cellsin vitro

Abstract

CGS-16949A is a new orally active nonsteroidal aromatase inhibitor which is more than 100-fold more potent than aminoglutethimide. This compound is an imidazole derivative, and therefore, its possible effect on cytochrome P-450 dependent enzyme activities in the adrenal gland was evaluated. In vitro investigations with dispersed normal and hyperplastic human adrenocortical cells showed that CGS-16949A at 10-7-10-6 M is a potent 11.beta.-hydroxylase inhibitor, which inhibits ACTH-stimulated cortisol release to a similar extent as an equimolar concentration of metyrapone (IC50 for both compounds, 10-7-5 .times. 10-7M). Etomidate was a more potent 11 .beta.-hydroxylase inhibitor (IC50, .apprx. 10-8 M), while 10-7-10-6 M ketoconazole caused (via 17.alpha.-hydroxylase inhibition) a similar inhibition of cortisol release as 10-7 M CGS-16949A (IC50, 10-7-5 .times. 10-7 M). The 11.beta.-hydroxylase inhibition by CGS-16949A was accompanied by a dose-dependent increase in the release of precursor steroids by the adrenocortical cells in vitro, including deoxycortisol, 17-hydroxyprogesterone, and androstenedione. Aldosterone release was suppressed 50% by 10-9 M CGS-16949A, while the IC50 for cortisol in the same cells was 10-7 M. Aldosterone release by the dispersed adenoma cells obtained from a patient with primary aldosteronism was also significantly suppressed by CGS-16949A. We conclude that 1) the new nonsteroidal aromatase inhibitor CGS 16949A is an inhibitor of 11.beta.-hydroxylase which is equipotent to metyrapone. At present it is unclear whether the compound at the dose that causes complete aromatase inhibition in vivo also affects stress-induced cortisol release in man. 2) CGS-1694A exerts a very potent inhibitory effect on normal aldosterone release (IC50, 10-9 M) and on tumorous aldosterone secretion. CGS-1694A might, therefore, be a drug that can be used in the treatment of primary hyperaldosteronism.