osilodrostat and Hypertension

Members of the CYP11B subfamily participate in the biosynthesis of important steroid hormones. CYP11B1 catalyzes the formation of cortisol, while CYP11B2 realizes the biosynthesis of aldosterone. Overproduction of cortisol is related to Cushing's disease, whereas overproduction of aldosterone leads to hypertension and end-organ damage such as cardiac and renal hypertrophy. Therefore, CYP11B1 and CYP11B2 have been defined as interesting targets for the development of novel drugs.. The paper describes the CYP11B1 and CYP11B2 genes and proteins, giving special attention to their functional and structural properties, the development of efficient test systems for potential inhibitors of both CYPs and the development and testing of novel potential drugs on the basis of selective inhibition of CYP11B1 and CYP11B2.. The availability of relevant and efficient screening systems for testing the effects of inhibitors of human CYP11B1 and CYP11B2, combined with experiences and success in synthesizing selective and efficient inhibitors of these isoenzymes, provides a realistic basis for a successful development of drugs using CYP11B1 and CYP11B2 as targets. The first clinical trials with the CYP11B2 inhibitor LCI699 demonstrated some side effects but showed inhibition of end-organ damage in animals, indicating that it might be a useful lead compound for future developments.

Topics: Aldosterone; Animals; Cardiomegaly; Cytochrome P-450 CYP11B2; Drug Design; Humans; Hypertension; Imidazoles; Isoenzymes; Kidney Diseases; Molecular Targeted Therapy; Pyridines; Steroid 11-beta-Hydroxylase

This study reviews the available data from randomized controlled trials on efficacy and safety of LCI699, a novel inhibitor of aldosterone synthase, as treatment of hypertension.. We performed a meta-analysis of phase II randomized, controlled trials comparing the efficacy/safety of LCI699 with placebo in hypertension patients. For this purpose, PubMed, Embase, Cochrane Library database, ISI-Science Citation Index, and the Chinese Biomedicine Literature Database were searched until August 2013. The available data on mean sitting systolic blood pressure (MSSBP), mean sitting diastolic blood pressure (MSDBP), adverse effects, renin-angiotensin-aldosterone system biomarkers (RAASB) and adrenocorticotropic hormone-stimulated cortisol concentration (AHSC) were collected. All data were analyzed using Review Manager, version 5.2.. The present study finally included three randomized controlled trials, comprising of 623 patients in total. The daily use of ≥ 1 mg LCI699 was associated with a significant reduction of MSSBP (Weighted mean difference/WMD = -8.80, 95% CI: -11.31 to -5.68, p < 0.00001, I2 = 0%) and MSDBP (WMD = -4.94, 95% CI: -7.49 to -2.40, p = 0.00001, I2 = 9%). Adverse reactions occurred in 73 of the 139 patients (52.51%) treated with LCI699 and in 34 of the 63 patients (53.96%) treated with placebo. Pooled meta-analysis showed that the use of LCI699 was associated with no increased risk of side effects compared with placebo (RR = 0.90; 95% CI: 0.68 to 1.18, p = 0.43, I2 = 0%). Suppression of plasma aldosterone was measured at all doses of LCI699 treatment groups. LCI699 suppressed the ACTH-stimulated cortisol response in a dose- and time-dependent manner.. Current evidence indicates that the novel aldosterone inhibitor LCI699 is an effective and well-tolerated antihypertensive agent that lowers plasma aldosterone concentration and produces a mild ACTH-stimulated cortisol response suppressive effect.

Topics: Adult; Antihypertensive Agents; Clinical Trials, Phase II as Topic; Cytochrome P-450 CYP11B2; Female; Humans; Hypertension; Imidazoles; Multicenter Studies as Topic; Pyridines; Randomized Controlled Trials as Topic

Aldosterone synthase (CYP11B2) inhibition has emerged as a new option for the treatment of hypertension, heart failure and renal disorders, in addition to mineralocorticoid receptor (MR) blockade. The aim is to decrease aldosterone concentrations in both plasma and tissues, thereby decreasing MR-dependent and MR-independent effects in the cardiac, vascular and renal target organs. LCI699 was the first orally active aldosterone-synthase inhibitor to be developed for human use. Its structure is similar to that of FAD286, the dextroenantiomer of the aromatase inhibitor, fadrozole. It dose-dependently decreases plasma and urine aldosterone concentrations by up to 70 or 80% and increases plasma renin activity in healthy male subjects on a low-sodium diet. LCI699 does not decrease basal plasma cortisol concentrations at doses of 0.5-3 mg q.d., but it blocks the cortisol response to adrenocorticotropic hormone (ACTH) at doses ≥ 3 mg q.d. In a proof-of-concept study in patients with primary aldosteronism (PA), LCI699 (0.5-1 mg b.i.d.) induced a dose-dependent and reversible 70-80% decrease in plasma and urinary aldosterone concentration accompanied by a massive dose-dependent accumulation of deoxycorticosterone (>+700%), the aldosterone precursor, in the plasma, thereby confirming the inhibition of the CYP11B2 gene product. This effect was associated with a rapid correction of hypokalaemia, a modest decrease in blood pressure (BP) and a mild increase in plasma renin concentration in patients with PA. LCI699 administration induced biological signs of partial inhibition of the glucocorticoid axis, such as dose-dependent increases in both plasma ACTH and 11-deoxycortisol (the precursor of cortisol) concentrations, consistent with the inhibition of the CYP11B1 gene product. An 8-week placebo-controlled dose-response study on patients with Stage 1 and 2 essential hypertension reported an optimal decrease in BP with a dose of 1 mg LCI699 q.d., which had an antihypertensive effect similar to that of 50 mg b.i.d. eplerenone. A blunted cortisol response to ACTH was observed in 20% of patients, but the clinical and biological safety and tolerability of LCI699 were similar to those of placebo and eplerenone. The discovery of this first orally active aldosterone synthase inhibitor, LCI699, has provided new opportunities to assess the feasibility and the haemodynamic, biological and safety consequences as well as the limitations of this new approach to block the aldosterone p

Topics: Aldosterone; Antihypertensive Agents; Cytochrome P-450 CYP11B2; Enzyme Inhibitors; Humans; Hypertension; Imidazoles; Pyridines; Steroid 11-beta-Hydroxylase

Aldosterone inhibition with mineralcorticoid receptor antagonists (MRAs) is an effective treatment for resistant hypertension. Aldosterone synthase inhibitors (ASIs) are currently being investigated as a new therapeutic strategy to reduce aldosterone secretion from the adrenal gland. In this study, the efficacy and safety of the first-generation ASI LCI699 (0.25 mg twice daily, 1 mg 4 once daily, and 0.5 mg/1 mg twice daily) was compared with placebo and eplerenone (50 mg twice daily), in patients with resistant hypertension. Placebo-adjusted decreases in systolic blood pressure (BP) with LCI699 ranged from 2.6 mm Hg to 4.3 mm Hg at week 8; changes in diastolic BP ranged from +0.3 mm Hg to -1.2 mm Hg. However, reductions were smaller than observed with eplerenone 50 mg twice daily (9.9 mm Hg and 2.9 mm Hg for systolic and diastolic BP, respectively) and not statistically significant vs placebo. LCI699 suppressed plasma aldosterone levels in a dose-related manner with corresponding dose-dependent increases in plasma renin activity and plasma 11-deoxycorticosterone. LCI699 and eplerenone were well tolerated. These data demonstrate that aldosterone synthesis inhibition with LCI699 lowers BP modestly in patients with resistant hypertension. Aldosterone synthesis inhibition might offer an attractive adjunct to aldosterone receptor blockade, although the potential of a combination MRA/ASI has not yet been tested.

Topics: Adolescent; Adult; Aged; Antihypertensive Agents; Blood Pressure; Cytochrome P-450 CYP11B2; Double-Blind Method; Eplerenone; Female; Humans; Hypertension; Iceland; Imidazoles; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Prospective Studies; Pyridines; Spironolactone; Treatment Outcome; United States; Young Adult

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

Topics: Adolescent; Adrenal Glands; Adult; Aged; Aldosterone; Antihypertensive Agents; Biomarkers; Blood Pressure; Cytochrome P-450 CYP11B2; Desoxycorticosterone; Double-Blind Method; Essential Hypertension; Female; Humans; Hydrocortisone; Hyperaldosteronism; Hypertension; Hypothalamus; Imidazoles; Male; Middle Aged; Prospective Studies; Pyridines; Renin-Angiotensin System; Steroid 11-beta-Hydroxylase; Treatment Outcome; Young Adult

Blockade of the renin-angiotensin-aldosterone system (RAAS) is an established method to lower blood pressure in patients with hypertension. Aldosterone, the end product of the RAAS cascade, acts by increasing salt reabsorption in the kidney and catecholamine release from the adrenal medulla. Currently available aldosterone inhibitors have the disadvantage of increasing circulating aldosterone and thus may lead to aldosterone breakthrough. Aldosterone synthase inhibition (ASI) is a novel approach to suppressing the RAAS. Due to homology between the enzymes responsible for aldosterone synthesis (CYP11B2) and cortisol synthesis (CYP11B1), the blockade of aldosterone synthesis may also suppress cortisol release. The authors evaluated the effect of the novel ASI LCI699 on the cortisol response to adrenocorticotropic hormone (ACTH) stimulation in patients with hypertension in order to find the maximally tolerated dose (MTD) in this patient population. Among the 63 patients evaluated, there was a dose- and time-dependent effect of LCI699 on both aldosterone and ACTH-stimulated cortisol. Based on exposure-response analysis, the MTD was estimated to be 1.30 mg once daily with a 90% prediction interval of 0.88 mg once daily to 1.81 mg once daily. No patients required intervention for adrenal insufficiency. LCI699 was well tolerated with no serious adverse events.

Topics: Adolescent; Adult; Aged; Aldosterone; Arterial Pressure; Cytochrome P-450 CYP11B2; Double-Blind Method; Female; Humans; Hydrocortisone; Hypertension; Imidazoles; Male; Middle Aged; Prospective Studies; Pyridines; Renin-Angiotensin System; Young Adult

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Topics: Cytochrome P-450 CYP11B2; Drug Design; Humans; Hyperaldosteronism; Hypertension; Imidazoles; Molecular Structure; Pyridines

Human clinical studies conducted with LCI699 established aldosterone synthase (CYP11B2) inhibition as a promising novel mechanism to lower arterial blood pressure. However, LCI699's low CYP11B1/CYP11B2 selectivity resulted in blunting of adrenocorticotropic hormone-stimulated cortisol secretion. This property of LCI699 prompted its development in Cushing's disease, but limited more extensive clinical studies in hypertensive populations, and provided an impetus for the search for cortisol-sparing CYP11B2 inhibitors. This paper summarizes the discovery, pharmacokinetics, and pharmacodynamic data in preclinical species and human subjects of the selective CYP11B2 inhibitor 8.

Topics: Aldosterone; Animals; Cytochrome P-450 CYP11B2; Enzyme Inhibitors; Halogenation; Haplorhini; Humans; Hypertension; Indoles; Methylation; Mineralocorticoid Receptor Antagonists; Pyridines; Rats; Rats, Sprague-Dawley; Sulfonamides