Can the dextroenantiomer of the aromatase inhibitor fadrozole be useful for clinical investigation of aldosterone-synthase inhibition?

Ménard, Joël; Pascoe, Leigh

doi:10.1097/01.hjh.0000226183.98439.b3

Cited by 29 publications

(14 citation statements)

References 73 publications

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“…LCI699 is a proprietary, first-generation aldosterone synthase inhibitor that was structurally derived from FAD286, the enantiomer of fadrozole that harbors minimal aromatase activity while retaining potent aldosterone synthase inhibitory activity [10].…”

Section: Introductionmentioning

confidence: 99%

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

Schumacher

Steele²,

Brunner³

2013

Journal of Hypertension

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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.

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Section: Introductionmentioning

confidence: 99%

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

Schumacher

Steele²,

Brunner³

2013

Journal of Hypertension

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“…FAD286 (the R-enantiomer of fadrozole; 4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzonitrile) (Santen et al, 1991;Ménard and Pascoe, 2006) and LCI699 (4-[(5R)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl]-3-fluorobenzonitrile) (Amar et al, 2010;Calhoun et al, 2011) are examples of ASIs that have been evaluated in preclinical models (Fiebeler et al, 2005;Ménard et al, 2014) as well as in patients (Santen et al, 1991;Ménard and Pascoe, 2006;Amar et al, 2010;Calhoun et al, 2011). However, these molecules exhibit only modest selectivity for inhibition of human AS over CS, and have resulted in blunted cortisol responses when evaluated in patients (Santen et al, 1991;Amar et al, 2010), a likely reason for their clinical failure as selective AS inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Selectivity of BI 689648, a Novel, Highly Selective Aldosterone Synthase Inhibitor: Comparison with FAD286 and LCI699 in Nonhuman Primates

Weldon

Cerny

Gueneva-Boucheva

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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The mineralocorticoid aldosterone is an important regulator of blood pressure, volume, and electrolyte balance. However, excess aldosterone can be deleterious as a driver of vascular remodeling and tissue fibrosis associated with cardiometabolic diseases. Aldosterone synthase (AS) inhibitors (ASI) attenuate the production of aldosterone directly and have been proposed as an alternative to mineralocorticoid receptor antagonists for blocking the pathologic effects of excess aldosterone. Discovery of selective ASIs has been challenging because of the high sequence identity (93%) AS shares with cortisol synthase (CS), and the low identity of rodent AS compared with human (63%). Using cynomolgus (cyno) monkey-based models, we identified BI 689648 [6-(5-methoxymethyl-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide], a novel, highly selective ASI that exhibits an in vitro IC 50 of 2 nM against AS and 300 nm against CS (150-fold selectivity) compared with the recently described ASIs FAD286 [4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzonitrile] (3 nM AS; 90 nM CS; 40-fold) and LCI699 (4-[(5R)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl]-3-fluorobenzonitrile) (10 nM AS; 80 nM CS; 8-fold). After oral administration in cyno monkeys, BI 689648 (5 mg/kg) exhibits a peak plasma concentration of ∼500 nM. For in vivo profiling we used an adrenocorticotropin-challenge model in which BI 689648 was .20-fold more selective compared with FAD286 and LCI699. Because both FAD286 and LCI699 failed to provide adequate selectivity for CS when tested in patients, the desire for more selective molecules to test the ASI hypothesis remains high. Therefore, highly selective aldosterone synthase inhibitors such as BI 689648 represent an important step forward toward developing ASIs with greater potential for clinical success in cardiometabolic diseases.

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“…An alternative therapeutic approach to prevent the deleterious effects of aldosterone is to suppress its production with inhibitors (ASI) of aldosterone synthase (CYP11B2), which catalyzes the final steps of aldosterone biosynthesis (Funder, 2006;Ménard and Pascoe, 2006). However, the preferred mechanism to block the effects of aldosterone is unknown.…”

mentioning

confidence: 99%

“…(ϩ)-(5R)-4- (5,6,7,pyridin-5-yl] benzonitrile hydrochloride (CGS020286A, FAD286, FAD) is a prototypical ASI that has undergone limited in vivo preclinical testing (Fiebeler et al, 2005;Minnaard-Huiban et al, 2008;Mulder et al, 2008;Lea et al, 2009) and has been recommended for clinical evaluation (Funder, 2006;Ménard and Pascoe, 2006;Siragy and Xue, 2008). FAD is the R-(ϩ)-enantiomer of the racemic CYP19 (aromatase) inhibitor CGS016949A (fadrozole), which is marketed in Japan as a treatment for estrogen-dependent breast cancer.…”

mentioning

confidence: 99%

Pharmacodynamic and Pharmacokinetic Characterization of the Aldosterone Synthase Inhibitor FAD286 in Two Rodent Models of Hyperaldosteronism: Comparison with the 11β-Hydroxylase Inhibitor Metyrapone

Rigel

Fu²,

Beil³

et al. 2010

J Pharmacol Exp Ther

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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.

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Can the dextroenantiomer of the aromatase inhibitor fadrozole be useful for clinical investigation of aldosterone-synthase inhibition?

Cited by 29 publications

References 73 publications

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

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

Selectivity of BI 689648, a Novel, Highly Selective Aldosterone Synthase Inhibitor: Comparison with FAD286 and LCI699 in Nonhuman Primates

Pharmacodynamic and Pharmacokinetic Characterization of the Aldosterone Synthase Inhibitor FAD286 in Two Rodent Models of Hyperaldosteronism: Comparison with the 11β-Hydroxylase Inhibitor Metyrapone

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