Aldosterone synthase inhibition for the treatment of hypertension and the derived mechanistic requirements for a new therapeutic strategy

Christoph D Schumacher, Ronald E Steele, Hans R Brunner, Christoph D Schumacher, Ronald E Steele, Hans R Brunner

Abstract

Context: We describe the clinical investigation of the first generation aldosterone synthase inhibitor, LCI699, in patients with essential, uncontrolled, resistant, or secondary hypertension. LCI699 competitively reduced blood pressure at lower doses yet counterintuitive effects were observed at higher doses.

Objective and method: An extensive endocrine biomarker analysis was performed to better understand the pharmacological mechanism of the drug.

Results: The interference of LCI699 in the renin-angiotensin-aldosterone system occurred with limited target selectivity, as a dose-dependent compensatory stimulation of the hypothalamic-pituitary-adrenal feedback axis was discovered. Thus, LCI699 affected two endocrine feedback loops that converged at a single point, inhibiting the 11β-hydroxylase reaction in the adrenal gland, leading to supraphysiological levels of 11-deoxycortiscosterone. The accumulation of this potent mineralocorticoid may explain the blunted blood pressure response to LCI699.

Conclusion: Future aldosterone synthase inhibitors may improve their target selectivity by sparing the 11β-hydroxylase reaction and preferentially inhibiting one of the two other enzymatic reactions mediated by aldosterone synthase.

Trial registration: ClinicalTrials.gov NCT00732771 NCT00758524 NCT00817414 NCT00817635.

Figures

FIGURE 1
FIGURE 1
(a) Regulatory endocrine feedback loops that control early and late adrenal steroidogenesis. (b–e) Diurnal variation of aldosterone secretion. Baseline hormone peak times of melatonin (b), plasma renin activity (PRA) (c), aldosterone (d), and cortisol (e) . 11β-OHase, 11β-hydroxylase; 11-DC, 11-deoxycortisol; 11-DOC, 11-deoxycorticosterone; 17-OH-Preg, 17-hydroxypregnenolone; 17-OH-Prog, 17-hydroxyprogesterone; 18-OH-corticosterone, 18-hydroxycorticosterone; A4, androstenedione; ACTH, adrenocorticotropin; Ang, angiotensin; Chol, cholesterol; CMO, corticosterone methyl oxidase; CRH, corticotropin-releasing hormone; DHEA, dehydroepiandrosterone; K, potassium; Na, sodium; Preg, pregnenolone; Prog, progesterone; PVN, paraventricular nucleus; RAAS, renin–angiotensin–aldosterone system. Figure 1b–e reproduced with permission .
FIGURE 2
FIGURE 2
Plasma biomarkers derived from study CLCI6992201 in essential hypertension. (a) Aldosterone; (b) potassium; (c) plasma renin activity (PRA); (d) sodium; (e) cortisol; (f) 11-deoxycortisol; (g) adrenocorticotrophic hormone (ACTH); (h) 11-deoxycorticosterone. BL, baseline value for the respective adjacent study arm to the right; EPL, eplerenone 50 mg twice daily; LCI, LCI699 applied at 0.25 mg once daily, 0.5 mg once daily, 1.0 mg once daily, 0.5 mg twice daily from left to right; PBO, placebo; REF, clinical reference value.
FIGURE 3
FIGURE 3
Plasma biomarkers derived from study CLCI699A2216 in resistant hypertension. (a) Aldosterone; (b) potassium; (c) plasma renin activity (PRA); (d) sodium; (e) cortisol; (f) 11-deoxycortisol; (g) adrenocorticotrophic hormone (ACTH); (h) 11-deoxycorticosterone. BL, baseline value for the respective adjacent study arm to the right; EPL, eplerenone 50 mg twice daily; LCI, LCI699 applied at 0.25 mg twice daily, 1.0 mg once daily, 0.5 mg/1.0 mg twice daily from left to right; PBO, placebo; REF, clinical reference value.
FIGURE 4
FIGURE 4
LCI699, in contrast to fadrozole, is primarily an 11β-hydroxylase inhibitor. X indicates the suspected enzyme inhibitory step for LCI699. The comparison of LCI699 with fadrozole is a dose compilation of clinical studies with LCI699 described herein and fadrozole reference data. BL, baseline value for the respective adjacent LCI699 study arm to the right; Fadr, fadrozole applied at 2.0 mg twice daily (derived from a healthy volunteer study published by Trunet et al. 1992 [17]); LCI, LCI699 applied at 0.25 mg twice daily (derived from study CLCI6992216), 0.5 mg twice daily (derived from study CLCI699A2201), and 1.0 mg twice daily (derived from study CLCI699A2215); PBO, placebo control for the fadrozole study arm; REF, clinical reference value.

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