Aldosterone Synthase Inhibition With LCI699

Amar, Laurence; Azizi, Michel; Ménard, Joël; Peyrard, Séverine; Watson, Catherine E.; Plouin, Pierre‐François

doi:10.1161/hypertensionaha.110.157271

Cited by 159 publications

(65 citation statements)

References 38 publications

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“…17 It was found that 7n provided selective reduction of plasma aldosterone levels without an effect on baseline morning cortisol levels. 15,16 However, suppression of stimulated cortisol levels was seen at doses above 0.5 mg, which can be attributed to the modest selectivity for CYP11B2 over CYP11B1.…”

Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 99%

“…In human studies, treatment with 7n was well tolerated and effective in reducing aldosterone levels to provide sustained lowering of blood pressure in patients with primary aldosteronism, 15 primary hypertension, 16 and resistant hypertension. 17 It was found that 7n provided selective reduction of plasma aldosterone levels without an effect on baseline morning cortisol levels.…”

Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 99%

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Discovery and in Vivo Evaluation of Potent Dual CYP11B2 (Aldosterone Synthase) and CYP11B1 Inhibitors

Meredith

Ksander

Monovich

et al. 2013

ACS Med. Chem. Lett.

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Aldosterone is a key signaling component of the renin-angiotensin-aldosterone system and as such has been shown to contribute to cardiovascular pathology such as hypertension and heart failure. Aldosterone synthase (CYP11B2) is responsible for the final three steps of aldosterone synthesis and thus is a viable therapeutic target. A series of imidazole derived inhibitors, including clinical candidate 7n, have been identified through design and structure−activity relationship studies both in vitro and in vivo. Compound 7n was also found to be a potent inhibitor of 11β-hydroxylase (CYP11B1), which is responsible for cortisol production. Inhibition of CYP11B1 is being evaluated in the clinic for potential treatment of hypercortisol diseases such as Cushing's syndrome. KEYWORDS: Inhibitor, CYP11B2, aldosterone synthase, aldosterone, hypertension, enzyme, CYP11B1, Cushing's syndrome, cortisol O ne of the primary functions of aldosterone through the mineralocorticoid receptor (MR) is to effect retention of sodium and excretion of potassium by the kidney.1 The elevation of aldosterone causes an increase in blood pressure as well as facilitating other cardiac, renal, and vascular damage. Activation of the renin-angiotensin system (RAS) induces aldosterone production. As such, MR antagonists have been used in the treatment of heart failure.2−4 While both RAS inhibitors and MR antagonists have been shown to reduce some of the pathological effects of aldosterone, there are noted drawbacks. In the case of RAS inhibition, a reduction of aldosterone is realized initially; however, this is not maintained. 5,6 Likewise, MR antagonists do not reduce the level of aldosterone, and in fact, they have been shown to induce aldosterone production.7 Thus, it was thought that there would be therapeutic benefit in directly inhibiting aldosterone production.Aldosterone is produced in the zona glomerulosa of the adrenal gland by the enzymatic action of aldosterone synthase (CYP11B2) on deoxycorticosterone. 8,9 Clinical observations suggested that the racemic aromatase (CYP19) inhibitor fadrazole affected aldosterone levels and subsequent preclinical studies demonstrated that the R-enantiomer (FAD286, Figure 1) was a potent inhibitor of CYP11B2.10 From this understanding we embarked on a program to investigate the structure−activity relationship of the FAD286 scaffold and to gain a more extensive understanding of the potential of aldosterone synthase inhibition to treat aldosterone-driven pathologies.Relatively little was known about the impact of substitution at R 1 , although we quickly realized that, as with FAD286, chirality at this point of attachment was important. The impact of altering the size of the saturated ring was not understood at the outset. Preliminary structure−activity relationships (SAR) around the phenyl ring indicated that R 2 would be a most promising site for optimization.In general the compounds from series I (n = 1), series II (n = 2), and series III (n = 3) were prepared as outlined in Scheme 1. Intermed...

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Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 99%

Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 99%

Discovery and in Vivo Evaluation of Potent Dual CYP11B2 (Aldosterone Synthase) and CYP11B1 Inhibitors

Meredith

Ksander

Monovich

et al. 2013

ACS Med. Chem. Lett.

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“…Moreover, the drug induced a blunted glucocorticoid response to ACTH of uncertain clinical significance. 81,82 …”

Section: Drug-based Treatment For Pamentioning

confidence: 99%

Outcomes of Drug-Based and Surgical Treatments for Primary Aldosteronism

Steichen

Lorthioir

Zinzindohoué

et al. 2015

Advances in Chronic Kidney Disease

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Treatments for primary aldosteronism (PA) aim to correct or prevent the deleterious consequences of hyperaldosteronism: hypertension, hypokalemia and direct target organ damage. Patients with unilateral PA considered fit for surgery can undergo laparoscopic adrenalectomy, which significantly decreases blood pressure and medications in most cases, and cures hypertension in about 40%. Mineralocorticoid receptor antagonists (MRA) are used to treat patients with bilateral PA and those with unilateral PA if surgery is not possible or not desired. Spironolactone is more potent than eplerenone, but high doses are poorly tolerated in men. MRA can be replaced or complemented with epithelial sodium channel blockers, such as amiloride. Thiazide diuretics and calcium channel blockers are used when the first-line drugs are insufficient to control blood pressure. Dietary sodium restriction should be implemented in all cases, because the deleterious consequences of hyperaldosteronism are dependent on salt loading. Several studies comparing the results of surgery and MRA have reported no differences in terms of blood pressure, serum potassium concentration or cardiovascular and renal outcomes, although the benefits of treatment tend to be observed sooner with surgery.PA patients display relative glomerular hyperfiltration, which is reversed by specific treatment, revealing chronic kidney disease in 30% of patients. However, further kidney damage is prevented by the treatment of PA. Clinical summary-The goals of treatment are the normalization of serum potassium concentration, blood pressure control and prevention of the direct effects of excess aldosterone on target organs. 3-The non-surgical treatment of PA is based on mineralocorticoid receptor antagonists and dietary sodium restriction.-Epithelial sodium channel blockers are used when mineralocorticoid receptor antagonists are not well tolerated; thiazide diuretics and calcium channel blockers are used when blood pressure control is insufficient with the first-line treatment.-Laparoscopic adrenalectomy is safe and decreases BP and medication requirements in patients with unilateral PA; drug-based treatments are appropriate in cases in which surgery is inappropriate or not desired.

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“…The initial reports of LCI699 explored its aldosterone synthase (CYP11B2) inhibitory action, at doses of up to 2 mg/d in patients with primary hyperaldosteronism and essential hypertension, and demonstrated correction of hypokalaemia and hypertension [63,64]. The induced hypoadrenalism precluded the use of this drug, but unleashed the development of clinical trials evaluating its efficacy and safety in the treatment of CD.…”

Section: Lci699mentioning

confidence: 99%