CS-3150, a novel non-steroidal mineralocorticoid receptor antagonist, prevents hypertension and cardiorenal injury in Dahl salt-sensitive hypertensive rats

Arai, Kiyoshi; Tsuruoka, Hiroyuki; Homma, Tomoyuki

doi:10.1016/j.ejphar.2015.11.028

Cited by 72 publications

(55 citation statements)

References 42 publications

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“…Esaxerenone is a nonsteroidal mineralocorticoid receptor blocker that has exhibited kidney protective effects superior to eplerenone in preclinical trials (16,17). This study showed that esaxerenone as add-on therapy to RASi in Japanese participants for 12 weeks reduced UACR by approximately one half in a dose-dependent manner.…”

Section: Discussionmentioning

confidence: 80%

“…Esaxerenone (CS-3150; Daiichi-Sankyo), a nonsteroidal mineralocorticoid receptor blocker, showed kidney protective effects in preclinical studies and may be added to existing treatments for patients with diabetic kidney disease (16,17). In a phase 1 study, the safety of a single dose and multiple doses of esaxerenone was confirmed in healthy Japanese subjects (18).…”

Section: Introductionmentioning

confidence: 99%

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Efficacy and Safety of Esaxerenone (CS-3150) for the Treatment of Type 2 Diabetes with Microalbuminuria

Ito

Shikata

Nangaku

et al. 2019

CJASN

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Background and objectives The progression of kidney disease in some patients with type 2 diabetes mellitus may not be adequately suppressed by renin-angiotensin system inhibitors. Esaxerenone (CS-3150) is a nonsteroidal mineralocorticoid receptor blocker that has shown kidney protective effects in preclinical studies, and it is a potential add-on therapy to treat diabetic kidney disease. This phase 2 study evaluated the efficacy and safety of esaxerenone in Japanese patients with type 2 diabetes mellitus and microalbuminuria.Design, setting, participants, & measurements This multicenter, randomized, double-blind, placebo-controlled trial enrolled 365 hypertensive or normotensive patients with type 2 diabetes mellitus and microalbuminuria (urinary albumin-to-creatinine ratio $45 to ,300 mg/g creatinine) treated with renin-angiotensin system inhibitor who had eGFR$30 ml/min per 1.73 m 2 . Participants were randomized to receive 0.625, 1.25, 2.5, or 5 mg/d esaxerenone or placebo for 12 weeks. The primary end point was the change in urinary albumin-tocreatinine ratio from baseline to week 12 (with last observation carried forward).Results Esaxerenone treatment at 1.25, 2.5, and 5 mg/d significantly reduced urinary albumin-to-creatinine ratio by the end of treatment (38%, 50%, and 56%, respectively) compared with placebo (7%; all P,0.001). The urinary albumin-to-creatinine ratio remission rate (defined as urinary albumin-to-creatinine ratio ,30 mg/g creatinine at the end of treatment and $30% decrease from baseline) was 21% in the 2.5-and 5-mg/d groups versus 3% for placebo (both P,0.05). Adverse events occurred slightly more frequently with esaxerenone versus placebo, but the frequencies of drug-related adverse events and discontinuation rates were similar in the placebo and the 0.625-, 1.25-, and 2.5-mg/d groups. Drug-related adverse events and treatment discontinuations were marginally higher in the 5-mg/d group. The most common drug-related adverse event was hyperkalemia, which was dose proportional.Conclusions Adding esaxerenone at 1.25, 2.5, and 5 mg/d for 12 weeks to an ongoing renin-angiotensin system inhibitor significantly reduces urinary albumin-to-creatinine ratio in patients with type 2 diabetes mellitus and microalbuminuria.

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Section: Discussionmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Efficacy and Safety of Esaxerenone (CS-3150) for the Treatment of Type 2 Diabetes with Microalbuminuria

Ito

Shikata

Nangaku

et al. 2019

CJASN

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“…Esaxerenone, a novel nonsteroidal MR blocker, shows high affinity and potency as well as great selectivity to MR in vitro and also strong antihypertensive and renoprotective effects in vivo . In this paper, we explained its high potency as well as great selectivity via crystallographic study.…”

Section: Discussionmentioning

confidence: 99%

“…These nuclear receptors share high sequence homology, and it has thus long been a challenge to obtain a selective antagonist for MR. Esaxerenone, a novel nonsteroidal MR blocker, was identified in order to overcome the limitations of spironolactone and eplerenone in clinical settings. Esaxerenone is a competitive MR blocker with high potency and selectivity in vitro and shows great antihypertensive and renoprotective effects in salt‐sensitive hypertensive rats . In contrast to spironolactone or eplerenone, esaxerenone is a pyrrole derivative and does not have a steroid structure.…”

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confidence: 99%

Crystal structure of the mineralocorticoid receptor ligand‐binding domain in complex with a potent and selective nonsteroidal blocker, esaxerenone (CS‐3150)

et al. 2020

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Activation of the mineralocorticoid receptor (MR) has long been considered a risk factor for cardiovascular diseases. It has been reported that the novel MR blocker esaxerenone shows high potency and selectivity for MR in vitro as well as great antihypertensive and renoprotective effects in salt-sensitive hypertensive rats. Here, we determined the cocrystal structure of the MR ligand-binding domain (MR-LBD) with esaxerenone and found that esaxerenone binds to MR-LBD in a unique manner with large side-chain rearrangements, distinct from those of previously published MR antagonists. This structure also displays an antagonist form that has not been observed for MR previously. Such a unique binding mode of esaxerenone provides great insight into the novelty, potency, and selectivity of this novel antihypertensive drug.The mineralocorticoid receptor (MR) is a steroidal hormone-activated nuclear receptor that has received increasing attention as a driver of cardiovascular and renal injury. Substantial clinical evidence has been accumulated showing that the blockade of MR is an important treatment option for not only hypertension [1,2], but also heart failure [3-5] and chronic kidney diseases including diabetic nephropathy [6][7][8]. Although two MR antagonists with steroidal structures, spironolactone and eplerenone, are now clinically available, their clinical use has not been widely accepted because of safety and efficacy concerns. Spironolactone has poor selectivity over progesterone receptor (PR) and androgen receptor (AR), which causes side effects such as painful gynecomastia, menstrual irregularities, and impotence. Eplerenone has better selectivity but in compromise it has relatively low potency against MR and is contraindicated in patients with renal impairment due to the risk of hyperkalemia.Within the nuclear receptor superfamily, MR, PR, AR, and glucocorticoid receptor (GR) belong to the estrogen receptor-like subfamily, 3-ketosteroid receptor group (NR3C) [9]. These nuclear receptors share high sequence homology, and it has thus long been a Abbreviations AR, androgen receptor; GR, glucocorticoid receptor; MR, mineralocorticoid receptor; MR-LBD, MR ligand-binding domain; PR, progesterone receptor; SBDD, structure-based drug design.

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“…The effect of MR blockade in the development of hypertension has been also assessed in experimental models. In the Dahl salt-sensitive model, MRA attenuated the progressive rise in systolic BP in rats fed with a high-salt diet [88,89]. Whole body disruption of MR in mice results in neonatal lethality from dehydration by renal Na + and water loss; thus, transgenic mouse models allowing cell-specific targeting of MR expression have been used to understand the role of MR in vascular tissues and its potential implication in BP regulation.…”

Section: Vascular Mr and Hypertensionmentioning

confidence: 99%

Mineralocorticoid Receptor in Calcium Handling of Vascular Smooth Muscle Cells

Salazar-Enciso¹,

Camacho-Concha²,

Mesquita³

et al. 2018

Calcium and Signal Transduction

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For decades, the mineralocorticoid receptor (MR) antagonists have been used for the management of cardiovascular diseases; however, the molecular mechanisms involved in their beneficial effects are not fully understood. Recent publications point to the fundamental role of aldosterone and vascular MR in the regulation of arterial tone, vascular contractility, and cell proliferation. However, the intricate transduction machinery activated by vascular MRs has begun to be revealed with the help of transgenic rodent models and novel transcriptional analysis approaches. Specifically, in this chapter, we review and discuss the most recent contributions about the fine-tuning that the MR exerts on the expression and function of ion channels that participate in calcium handling of vascular cells and the therapeutic implications for hypertension and cardiovascular diseases.

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CS-3150, a novel non-steroidal mineralocorticoid receptor antagonist, prevents hypertension and cardiorenal injury in Dahl salt-sensitive hypertensive rats

Cited by 72 publications

References 42 publications

Efficacy and Safety of Esaxerenone (CS-3150) for the Treatment of Type 2 Diabetes with Microalbuminuria

Efficacy and Safety of Esaxerenone (CS-3150) for the Treatment of Type 2 Diabetes with Microalbuminuria

Crystal structure of the mineralocorticoid receptor ligand‐binding domain in complex with a potent and selective nonsteroidal blocker, esaxerenone (CS‐3150)

Mineralocorticoid Receptor in Calcium Handling of Vascular Smooth Muscle Cells

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