**8.2 Aldosterone synthase inhibitors**

The other new class of anti-aldosterone agents includes the selective aldosterone-synthase inhibitors. Aldosterone synthase or CYP11B2 is an enzyme of the cytochrome P450 family with steroid 18-hydroxylase and 18-oxidase properties. It catalyzes the formation of aldosterone from 11-deoxycorticosterone within the zona glomerulosa in the adrenal cortex (Figure 3). CYP11B2 deficiency in humans is characterized by a low/absent aldosterone synthesis in the adrenal cortex, high plasma renin activity and is responsible for a sodiumwasting phenotype associated with retarded growth. Conversely, enhanced activation of CYP11B2 as it is supposed to occur in the polymorphism 344C/T, is associated with

combination and chlorthalidone alone. Therefore current evidence does not support any effect of low doses of triamterene on blood pressure. No data are currently available on the effects on blood pressure of higher doses of triamterene and therefore a dose-response relationship with the hypotensive effect can not be demonstrated. No effects of triamterene on pulse pressure or blood pressure variability could be demonstrated in the studies that have employed this agent in the treatment of hypertension. Tolerability and safety profile of

There are no studies that have tested the effects of triamterene in other disease conditions. In primary aldosteronism experiences are mainly anedoctal and the doses of this drug that should be used in this endocrine disorder have never been specifically defined. No studies have been conducted to investigate the effects of triamterene on subclinical hypertensive

Promising results with mineralocorticoid receptor antagonists in the treatment of hypertension and prevention of hypertension-related organ damage have prompted the search and possible development of new aldosterone antagonists. Search has followed two main strategies: the first has consisted in the development of non-steroidal antagonists that could overcome the side effects of spironolactone and canrenoate without losing the pharmacological properties of these compounds; the second has aimed at developing drugs that inhibit aldosterone biosynthesis and has resulted in the generation of aldosterone

The first strategy moved its initial steps from the demonstration that some dyhydropyridine calcium-channel blockers (CCBs) exerts also a mineralocorticoid receptor antagonist activity. Researchers in the Pfizer® laboratories reported that nimodipine, felodipine, and nitrendipine block aldosterone-induced receptor activation by competing with aldosterone binding to the receptor "ligand binding domain". The affinity of dihydropyridines for the receptor binding domain is lower than for the L-type calcium channels, indicating that inhibition of mineralocorticoid receptor activity is independent of the effects on calcium channels. The efficacy of dyihydropyridines as mineralocorticoid receptor antagonist is comparable to that of eplerenone, whereas non-dihydropyridine CCBs such as verapamil

The other new class of anti-aldosterone agents includes the selective aldosterone-synthase inhibitors. Aldosterone synthase or CYP11B2 is an enzyme of the cytochrome P450 family with steroid 18-hydroxylase and 18-oxidase properties. It catalyzes the formation of aldosterone from 11-deoxycorticosterone within the zona glomerulosa in the adrenal cortex (Figure 3). CYP11B2 deficiency in humans is characterized by a low/absent aldosterone synthesis in the adrenal cortex, high plasma renin activity and is responsible for a sodiumwasting phenotype associated with retarded growth. Conversely, enhanced activation of CYP11B2 as it is supposed to occur in the polymorphism 344C/T, is associated with

triamterene in the studies that have tested this drug were acceptable.

**8.1 Non steroidal mineralocorticoid receptor antagonists** 

and diltiazem do not have any inhibitory activity.

**8.2 Aldosterone synthase inhibitors** 

organ damage, heart failure, and proteinuria.

**8. New aldosterone blockers** 

synthase direct inhibitors.

increased left ventricular mass and greater risk to develop hypertension. Since CYP11B2 activity is the limiting biochemical step in aldosterone synthesis, its selective inhibition is a good target for prevention of aldosterone untoward effects mediated by both mineralocorticoid receptor-dependent and mineralocorticoid receptor-independent pathways.

At present, only two compounds (both synthesized by Novartis®) with selective CYP11B2 inhibitory properties have been tested in animal models and, very recently, in the clinical setting. FAD286 is the D-enantiomer of the fadrozole, an aromatase inhibitor developed to treat advanced breast cancer, that reduces aldosterone levels and increases plasma renin activity in rats fed with either low or high sodium diet. In a transgenic rat model of secondary hypertension in which the angiotensinogen gene is overexpressed and circulating angiotensin II levels are increased, oral administration of FAD286 has reduced mortality by 4 times. In transgenic rats treated with FAD286, cardiac hypertrophy, albuminuria, and histologic evidence of glomerular damage were less frequent than in control animals. Despite very minor effects of FAD286 on blood pressure, its effects on organ damage were comparable to those of the angiotensin receptor blocker, losartan.

Following promising preclinical results, the first aldosterone synthase inhibitor, LCI699, was tested in two phase-II clinical trials. LCI699 is similar in structure to FAD286 and it has been developed for human use. LCI699 was administered to 14 patients affected by primary aldosteronism and effects were compared to those of placebo. After 2 weeks of treatment, there was a dose-dependent decrease in plasma aldosterone and an increase in 11 deoxycorticosterone, potassium, and adrenocorticotropin levels. Treatment induced mild reduction of 24-h ambulatory systolic blood pressure by (4.1 mm Hg) after 4 weeks. More recently, Calhoun et al. have published the first randomized, double-blind, placebo controlled phase-II trial with LCI699 that was conducted in 524 patients with essential hypertension. In this trial different doses of LCI699 have reduced 24-h ambulatory systolic blood pressure, but only the highest dose has reduced also diastolic blood pressure.
