Pharmacological profile of CS-3150, a novel, highly potent and selective non-steroidal mineralocorticoid receptor antagonist

Arai, Kiyoshi; Homma, Tomoyuki; Morikawa, Yuka; Ubukata, Naoko; Tsuruoka, Hiyoyuki; Aoki, Kazumasa; Ishikawa, Hisatake; Mizuno, Makoto; Sada, Toshio

doi:10.1016/j.ejphar.2015.06.015

Cited by 113 publications

(103 citation statements)

References 39 publications

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“…In this study, repeated administration of CS-3150 for 4 weeks significantly inhibited the onset of hypertension in the DOCA rats, which was consistent with the results of our previous study for 2 weeks (Arai et al, 2015). SBP was measured by the tail-cuff method, which is a little less accurate than the telemetry method.…”

Section: Discussionsupporting

confidence: 80%

“…It is well known that deoxycorticosterone acetate (DOCA), a synthetic mineralocorticoid, induces hypertension and renal injury in combination with salt loading to rats (DOCA rats), and this hypertensive rat is widely used as an MR-mediated disease model to evaluate pharmacological effects of MR antagonists or other drugs (Klanke et al, 2008;Seifi et al, 2010). We have previously reported that CS-3150 inhibits elevation in systolic blood pressure (SBP) in DOCA rats (Arai et al, 2015); however, we have not examined the effects of CS-3150 on renal injury. In addition, it remains unclear whether CS-3150 elicits therapeutic efficacy in the established hypertension dx.doi.org/10.1124/jpet.116.234765. s This article has supplemental material available at jpet.aspetjournals.org.…”

Section: Introductionmentioning

confidence: 99%

“…CS-3150 is a selective and highly potent MR antagonist with long-lasting MR antagonism after oral administration (Arai et al, 2015). It is well known that deoxycorticosterone acetate (DOCA), a synthetic mineralocorticoid, induces hypertension and renal injury in combination with salt loading to rats (DOCA rats), and this hypertensive rat is widely used as an MR-mediated disease model to evaluate pharmacological effects of MR antagonists or other drugs (Klanke et al, 2008;Seifi et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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CS-3150, a Novel Nonsteroidal Mineralocorticoid Receptor Antagonist, Shows Preventive and Therapeutic Effects On Renal Injury in Deoxycorticosterone Acetate/Salt-Induced Hypertensive Rats

Arai

Morikawa

Ubukata

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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The present study was designed to assess both preventive and therapeutic effects of (S)-1-(2-Hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl) phenyl]-5-[2-(trifluoromethyl) phenyl]-1H-pyrrole-3-carboxamide (CS-3150), a novel nonsteroidal mineralocorticoid receptor antagonist, on renal injury in deoxycorticosterone acetate (DOCA)/salt-induced hypertensive rats (DOCA rats). From 7 weeks of age, DOCA was subcutaneously administered once a week for 4 weeks to uninephrectomized rats fed a high-salt diet. In experiment 1, CS-3150 (0.3-3 mg/kg) was orally administered once a day for 4 weeks coincident with DOCA administration. In experiment 2, after establishment of renal injury by 4 weeks of DOCA/salt loading, CS-3150 (3 mg/kg) was orally administered once a day for 4 weeks with or without continuous DOCA administration. In experiment 1, DOCA/salt loading significantly increased systolic blood pressure (SBP), which was prevented by CS-3150 in a dose-dependent manner. Development of renal injury (proteinuria, renal hypertrophy, and histopathological changes in glomeruli and tubule) was also suppressed by CS-3150 with inhibition of mRNA expression of fibrosis, inflammation, and oxidative stress markers. In experiment 2, under continuous DOCA treatment, CS-3150 clearly ameliorated existing renal injury without lowering SBP, indicating that CS-3150 regressed renal injury independent of its antihypertensive action. Moreover, CS-3150 treatment in combination with withdrawal of DOCA showed further therapeutic effect on renal injury accompanied by reduction in SBP. These results demonstrate that CS-3150 not only prevents but also ameliorates hypertension and renal injury in DOCA rats. Therefore, CS-3150 could be a promising agent for the treatment of hypertension and renal disorders, and may have potential to promote regression of renal injury.

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Section: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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CS-3150, a Novel Nonsteroidal Mineralocorticoid Receptor Antagonist, Shows Preventive and Therapeutic Effects On Renal Injury in Deoxycorticosterone Acetate/Salt-Induced Hypertensive Rats

Arai

Morikawa

Ubukata

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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“…2015 a ): Esaxerenone more potently blocked aldosterone-induced transcriptional activation of human MR in a cell-based assay with an IC 50 value of 3.7 nM compared to spironolactone and eplerenone, with IC 50 values of 66 and 970 nM respectively. Esaxerenone also showed at least a 1000-fold higher selectivity for MR over other steroid hormone receptors in vitro , a long half-life and a more pronounced antihypertensive activity induced by DOCA/salt-loading to rats than spironolactone or eplerenone (Arai et al 2015 a ). Chronic treatment of Dahl salt-sensitive hypertensive rats demonstrated a dose-dependent antihypertensive effect of esaxerenone with an equivalent reduction of blood pressure with a low dose of esaxerenone (0.5 mg/kg) to that of spironolactone (100 mg/kg) and eplerenone (100 mg/kg).…”

Section: Non-steroidal Mras (The Recent 15 Years Of Mra Randd)mentioning

confidence: 99%

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor antagonists: 60 years of research and development

Kolkhof

Bärfacker

2017

Journal of Endocrinology

202

165

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The cDNA of the mineralocorticoid receptor (MR) was cloned 30 years ago, in 1987. At that time, spirolactone, the first generation of synthetic steroid-based MR antagonists (MRAs), which was identified in preclinical in vivo models, had already been in clinical use for 30 years. Subsequent decades of research and development by Searle & Co., Ciba-Geigy, Roussel Uclaf and Schering AG toward identifying a second generation of much more specific steroidal MRAs were all based on the initial 17-spirolactone construct. The salient example is eplerenone, first described in 1987, coincidentally with the cloning of MR cDNA. Its launch on the market in 2003 paralleled intensive drug discovery programs for a new generation of non-steroidal MRAs. Now, 30 years after the cDNA cloning of MR and 60 years of clinical use of steroidal MRAs, novel non-steroidal MRAs such as apararenone, esaxerenone and finerenone are in late-stage clinical trials in patients with heart failure, chronic kidney disease (CKD), hypertension and liver disease. Finerenone has already been studied in over 2000 patients with heart failure plus chronic kidney disease and/or diabetes, and in patients with diabetic kidney disease, in five phase II clinical trials. Here, we reflect on the history of the various generations of MRAs and review characteristics of the most important steroidal and non-steroidal MRAs.

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“…Esaxerenone (CS-3150) is a novel, nonsteroidal, selective MR blocker. An in vitro study showed that esaxerenone inhibited the binding of aldosterone to the MR, with no agonistic or antagonistic effects on glucocorticoid, androgen, or progesterone receptors, even at high concentrations (Arai et al, 2015a). In pharmacology studies using rat models, esaxerenone was demonstrated to have potent and long-lasting antihypertensive and cardio-renal protective effects (Arai et al, 2015a(Arai et al, , b, 2016.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics, Metabolism, and Excretion of [¹⁴C]Esaxerenone, a Novel Mineralocorticoid Receptor Blocker in Humans

et al. 2018

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Esaxerenone (CS-3150) is a novel, nonsteroidal, selective mineralocorticoid receptor blocker. The absorption, metabolism, distribution, and excretion of esaxerenone were assessed in in vitro studies and in a clinical study, where [ 14 C]esaxerenone (150 mCi/ 20 mg) was administered orally to six healthy male subjects. The plasma concentrations of esaxerenone and its metabolites (M4, M11, and M1) were measured using liquid chromatographytandem mass spectrometry. The recovery of radioactivity was 92.5%, with 38.5% and 54.0% excreted in the urine and feces, respectively. The half-life of radioactivity in blood and plasma was approximately 30 hours, similar to that of the unchanged form in plasma. The blood-to-plasma ratio was 0.628, demonstrating low partitioning to blood components. In plasma, esaxerenone was the most abundant moiety (40.8%), followed by O-glucuronide (21.4%; M4), acyl-glucuronide of amide-bond hydrolysate (8.0%; M11), and the deshydroxyethyl form (1.7%; M1). In vitro studies showed that esaxerenone was a substrate of CYP3A and multiple UDPglucuronosyltransferase isoforms. Oxidation contributed approximately 30% to its clearance, as indicated by the excretion ratio of oxidized metabolites into urine and feces. Caco-2 studies showed that esaxerenone was a substrate of P-glycoprotein and breast cancer resistance protein; however, the excretion ratios of the unchanged form in the feces and urine were 18.7% and 1.6%, respectively, indicating that these transporters were not important for the absorption and elimination of esaxerenone. Low urinary excretion of esaxerenone suggested that the plasma exposure of esaxerenone was not affected by renal dysfunction. Multiple elimination pathways including oxidation, glucuronidation, and hydrolysis, and the low contribution of transporters, indicated limited drug-drug interaction potential. https://doi.org/10.1124/dmd.118.084897.s This article has supplemental material available at dmd.aspetjournals.org.

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Pharmacological profile of CS-3150, a novel, highly potent and selective non-steroidal mineralocorticoid receptor antagonist

Cited by 113 publications

References 39 publications

CS-3150, a Novel Nonsteroidal Mineralocorticoid Receptor Antagonist, Shows Preventive and Therapeutic Effects On Renal Injury in Deoxycorticosterone Acetate/Salt-Induced Hypertensive Rats

CS-3150, a Novel Nonsteroidal Mineralocorticoid Receptor Antagonist, Shows Preventive and Therapeutic Effects On Renal Injury in Deoxycorticosterone Acetate/Salt-Induced Hypertensive Rats

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor antagonists: 60 years of research and development

Pharmacokinetics, Metabolism, and Excretion of [¹⁴C]Esaxerenone, a Novel Mineralocorticoid Receptor Blocker in Humans

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Pharmacological profile of CS-3150, a novel, highly potent and selective non-steroidal mineralocorticoid receptor antagonist

Cited by 113 publications

References 39 publications

CS-3150, a Novel Nonsteroidal Mineralocorticoid Receptor Antagonist, Shows Preventive and Therapeutic Effects On Renal Injury in Deoxycorticosterone Acetate/Salt-Induced Hypertensive Rats

CS-3150, a Novel Nonsteroidal Mineralocorticoid Receptor Antagonist, Shows Preventive and Therapeutic Effects On Renal Injury in Deoxycorticosterone Acetate/Salt-Induced Hypertensive Rats

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor antagonists: 60 years of research and development

Pharmacokinetics, Metabolism, and Excretion of [14C]Esaxerenone, a Novel Mineralocorticoid Receptor Blocker in Humans

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Pharmacokinetics, Metabolism, and Excretion of [¹⁴C]Esaxerenone, a Novel Mineralocorticoid Receptor Blocker in Humans