Aldosterone synthase (CYP11B2) inhibitors (ASIs) represent an attractive therapeutic approach for mitigating the untoward effects of aldosterone. We characterized the pharmacokinetic/ pharmacodynamic relationships of a prototypical ASI, (ϩ)-(5R)-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl]benzonitrile hydrochloride (CGS020286A, FAD286, FAD) and compared these profiles to those of the 11␤-hydroxylase inhibitor metyrapone (MET) in two rodent models of secondary hyperaldosteronism and corticosteronism. In chronically cannulated Sprague-Dawley rats, angiotensin II (ANG II) (300 ng/kg bolus ϩ 100 ng/kg/ min infusion) or adrenocorticotropin (100 ng/kg ϩ 30 ng/kg/ min) acutely elevated plasma aldosterone concentration (PAC) from ϳ0.26 nM to a sustained level of ϳ2.5 nM for 9 h. Adrenocorticotropin but not ANG II elicited a sustained increase in plasma corticosterone concentration (PCC) from ϳ300 to ϳ1340 nM. After 1 h of Ang II or adrenocorticotropin infusion, FAD (0.01-100 mg/kg p.o.) or MET (0.1-300 mg/kg p.o.) doseand drug plasma concentration-dependently reduced the elevated PACs over the ensuing 8 h. FAD was ϳ12 times more dose-potent than MET in reducing PAC but of similar or slightly greater potency on a plasma drug concentration basis. Both agents also decreased PCC in the adrenocorticotropin model at relatively higher doses and with similar dose potencies, whereas FAD was 6-fold weaker based on drug exposures. FAD was ϳ50-fold selective for reducing PAC versus PCC, whereas MET was only ϳ3-fold selective. We conclude that FAD is a potent, orally active, and relatively selective ASI in two rat models of hyperaldosteronism. MET is an order of magnitude less selective than FAD but is, nevertheless, more potent as an ASI than as an 11␤-hydroxylase inhibitor.

BackgroundAldosterone synthase inhibition provides the potential to attenuate both the mineralocorticoid receptor-dependent and independent actions of aldosterone. In vitro studies with recombinant human enzymes showed LCI699 to be a potent, reversible, competitive inhibitor of aldosterone synthase (Ki = 1.4 ± 0.2 nmol/L in humans) with relative selectivity over 11β-hydroxylase.MethodsHormonal effects of orally administered LCI699 were examined in rat and monkey in vivo models of adrenocorticotropic hormone (ACTH) and angiotensin-II-stimulated aldosterone release, and were compared with the mineralocorticoid receptor antagonist eplerenone in a randomized, placebo-controlled study conducted in 99 healthy human subjects. The effects of LCI699 and eplerenone on cardiac and renal sequelae of aldosterone excess were investigated in a double-transgenic rat (dTG rat) model overexpressing human renin and angiotensinogen.ResultsRat and monkey in vivo models of stimulated aldosterone release predicted human dose– and exposure–response relationships, but overestimated the selectivity of LCI699 in humans. In the dTG rat model, LCI699 dose-dependently blocked increases in aldosterone, prevented development of cardiac and renal functional abnormalities independent of blood pressure changes, and prolonged survival. Eplerenone prolonged survival to a similar extent, but was less effective in preventing cardiac and renal damage. In healthy human subjects, LCI699 0.5 mg selectively reduced plasma and 24 h urinary aldosterone by 49 ± 3% and 39 ± 6% respectively (Day 1, mean ± SEM; P < 0.001 vs placebo), which was associated with natriuresis and an increase in plasma renin activity. Doses of LCI699 greater than 1 mg inhibited basal and ACTH-stimulated cortisol. Eplerenone 100 mg increased plasma and 24 h urinary aldosterone while stimulating natriuresis and increasing renin activity. In contrast to eplerenone, LCI699 increased the aldosterone precursor 11-deoxycorticosterone and urinary potassium excretion.ConclusionsThese results provide new insights into the cardiac and renal effects of inhibiting aldosterone synthase in experimental models and translation of the hormonal effects to humans. Selective inhibition of aldosterone synthase appears to be a promising approach to treat diseases associated with aldosterone excess.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-014-0340-9) contains supplementary material, which is available to authorized users.

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...