Aldosterone synthase inhibition: cardiorenal protection in animal disease models and translation of hormonal effects to human subjects

Abstract

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.

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

“…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.…”

Osilodrostat (LCI699), a potent 11β-hydroxylase inhibitor, administered in combination with the multireceptor-targeted somatostatin analog pasireotide: A 13-week study in rats

“…In addition to these cortisol-lowering actions, pasireotide and osilodrostat have been shown to exert a number of other pharmacological effects, including pasireotide-mediated suppression of GH secretion from the pituitary gland (Colao et al, 2012(Colao et al, , 2014 and osilodrostat-mediated inhibition of aldosterone synthase (Menard et al, 2010). The doses of osilodrostat and pasireotide studied in current combination are biologically relevant as similar or lower doses were shown to be pharmacologically active in previous rat studies (Silva et al, 2005;Menard et al, 2014).…”

Поліморфізм Гена Альдостеронсинтази При Аліментарному Ожирінні, Компонентах Метаболічного Синдрому, Деяких Формах Вторинних Артеріальних Гіпертензій І патології Кори Надниркових Залоз (Огляд Літератури)

“…Во избежание таких побочных эффектов и для снижения сывороточной концентрации АЛ и со-зданы ингибиторы альдостеронсинтазы (ИАС), представляющие собой новую терапевтическую опцию по предотвращению неблагоприятных эф-фектов антагонистов АЛ [67][68][69][70][71]. С учетом боль-шой значимости проблемы разработаны новые препараты -ингибиторы АСFAD286 и LCI699, но и они также недостаточно специфичны в отно-шении CYP11B2 в сравнении с 11β-гидроксилазой (CYP11B1).…”

“…С учетом боль-шой значимости проблемы разработаны новые препараты -ингибиторы АСFAD286 и LCI699, но и они также недостаточно специфичны в отно-шении CYP11B2 в сравнении с 11β-гидроксилазой (CYP11B1). Позитивный эффект ИАС доказан в эксперименте [67,71].…”

“…Следующее поколение ИАС должно снижать уровень АЛ в крови, подавляя фермент, отвечающий за его синтез, -АС. Новые инги-биторы АС будут не только эффективно снижать АД, но и предотвращать развитие неблагопри-ятных последствий, продлевая жизнь пациентов и способствуя снижению высокого уровня общей смерт ности от данной патологии [70,71].…”