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 X 10(-7) M). Etomidate was a more potent 11 beta-hydroxylase inhibitor (IC50, approximately 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 X 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 concluded 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-16949A exerts a very potent inhibitory effect on normal aldosterone release (IC50, 10(-9) M) and on tumorous aldosterone secretion. CGS-16949A might, therefore, be a drug that can be used in the treatment of primary hyperaldosteronism.

In Vivo Active Aldosterone Synthase Inhibitors with Improved Selectivity: Lead Optimization Providing a Series of Pyridine Substituted 3,4-Dihydro-1H-quinolin-2-one Derivatives

“…The inhibitory activities of the compounds were determined in V79 MZh cells expressing either human CYP11B2 or CYP11B1. 10 ability to reduce corticoid formation in vitro 29 and in vivo, 30 was used as a reference (CYP11B2, IC 50 ) 1 nM; CYP11B1, IC 50 ) 10 nM).…”

Aldosterone Synthase Inhibition With LCI699

“…7 Aldosterone synthase inhibition has, thus, emerged as a new therapeutic option aimed at decreasing hormone concentrations in both plasma and tissues, thus reducing both its MR receptor-dependent and -independent effects 1,6,7 at the level of renal epithelial cells and cardiac and vascular target organs. Fadrozole, an aromatase inhibitor with inhibitory properties against aldosterone synthase, 18,19 and its dextroenantiomer FAD286 have been experimentally tested preclinically, 20 -24 but this potential therapeutic approach has never been investigated in patients.…”

Can the dextroenantiomer of the aromatase inhibitor fadrozole be useful for clinical investigation of aldosterone-synthase inhibition?

“…Early investigation showed that it was not as potent an aromatase inhibitor as expected, and was certainly less potent than the subsequently developed letrozole, anastrozole and exemestane [28][29][30]. Furthermore, it was not specific, as it has an inhibitory effect on aldosterone synthesis [31]. At a daily dose of 16 mg, fadrozole induced a significant increase in the blood 18-hydroxycorticosterone/aldosterone ratio, consistent with an aldosterone-synthase inhibition [32].…”