title: Aldosterone synthase inhibition: cardiorenal protection in animal disease models and translation of hormonal effects to human subjects.
abstract: BACKGROUND
  Aldosterone 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 (K i = 1.4 ± 0.2 nmol/L in humans) with relative selectivity over 11β-hydroxylase.
  
  
  METHODS
  Hormonal 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.
  
  
  RESULTS
  Rat 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.
  
  
  CONCLUSIONS
  These 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.
authors.affiliation: Université Paris Descartes, Faculté de Médecine and INSERM/AP-HP Clinical Investigation Center, Georges Pompidou Hospital, Paris, France. joel.menard@crc.jussieu.fr.
authors.forename: Joël
authors.initials: J
authors.lastname: Ménard
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. dean.rigel@novartis.com.
authors.forename: Dean F
authors.initials: DF
authors.lastname: Rigel
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA, USA. catherine.watson@novartis.com.
authors.forename: Catherine
authors.initials: C
authors.lastname: Watson
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. a.jeng@verizon.net.|Current address: Golda Och Academy, 1418 Pleasant Valley Way, West Orange, NJ, 07052, USA. a.jeng@verizon.net.
authors.forename: Arco Y
authors.initials: AY
authors.lastname: Jeng
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. fumin.fu@novartis.com.
authors.forename: Fumin
authors.initials: F
authors.lastname: Fu
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. michael.beil@novartis.com.
authors.forename: Michael
authors.initials: M
authors.lastname: Beil
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. jing.liu@novartis.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. wei.chen@novartis.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. chii-whei.hu@novartis.com.
authors.forename: Chii-Whei
authors.initials: CW
authors.lastname: Hu
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. jennifer.leung-chu@novartis.com.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Leung-Chu
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. daniel.lasala@novartis.com.
authors.forename: Daniel
authors.initials: D
authors.lastname: LaSala
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA, USA. guiqing.liang@novartis.com.
authors.forename: Guiqing
authors.initials: G
authors.lastname: Liang
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. sam.rebello@novartis.com.
authors.forename: Sam
authors.initials: S
authors.lastname: Rebello
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. yiming.zhang@novartis.com.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA, USA. wpdole47@gmail.com.
authors.forename: William P
authors.initials: WP
authors.lastname: Dole
mesh_terms: D000808:Angiotensinogen / Q000502:physiology*; D000818:Animals; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D004311:Double-Blind Method; D000077545:Eplerenone; D000882:Haplorhini; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D010919:Placebos; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D012083:Renin / Q000502:physiology*; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D057170:Translational Research, Biomedical
chemical_list: D007093:Imidazoles; D010919:Placebos; D011725:Pyridines; D000808:Angiotensinogen; D013148:Spironolactone; C553306:Osilodrostat; D000077545:Eplerenone; D019405:Cytochrome P-450 CYP11B2; D012083:Renin