Mineralocorticoid Receptor Antagonists

Nordqvist, Anneli; Granberg, Kenneth L.

doi:10.1016/bs.vh.2018.10.008

Cited by 6 publications

(8 citation statements)

References 58 publications

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“…C). In addition, other reported cocrystal structures of MR‐LBD with nonsteroidal MR antagonists showed similar binding modes, which mimicked that of the steroid antagonists .…”

Section: Resultsmentioning

confidence: 54%

“…Among several clinical candidates of nonsteroidal MR antagonists , the cocrystal structures of AZD9977 and its derivatives have been reported in detail . According to the reported structures, the binding mode of these compounds well mimics that of steroid compounds such as spironolactone, despite not sharing the same chemical structure as steroids.…”

Section: Resultsmentioning

confidence: 99%

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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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“…C). In addition, other reported cocrystal structures of MR‐LBD with nonsteroidal MR antagonists showed similar binding modes, which mimicked that of the steroid antagonists .…”

Section: Resultsmentioning

confidence: 54%

Section: Resultsmentioning

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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“…MR antagonists decrease the aldosterone effect by binding to the mineralocorticoid receptor and therefore inhibiting aldosterone biological activity. This leads to higher levels of potassium in serum and increased sodium excretion, resulting in decreased body fluid and lower blood pressure (Nordqvist and Granberg 2019). These class of drugs has shown a beneficial effect in various animal models of disease as well as in several clinical trials and represent potential prevention therapy for patients at risk of ischemic stroke (Weldon and Brown 2019; Namsolleck and Unger 2014).…”

Section: Aldosterone Inhibitors -Structure and Mechanism Of Actionmentioning

confidence: 99%

The role of aldosterone inhibitors in cardiac ischemia–reperfusion injury

Dragasevic

Jakovljević

Živković

et al. 2021

Can. J. Physiol. Pharmacol.

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Myocardial ischaemia-reperfusion (I/R) injury is well known term for paradoxal exacerbation of cellular destruction and dysfunction, after the restoration of blood flow to previously ischaemic heart. A vast number of studies that has demonstrated the role of mineralocorticoids in cardiovascular diseases is based on the use of pharmacological mineralocorticoid receptor antagonists (MRA) such as spironolactone and eplerenone. This review paper aimed to summarize current knowledge on the effects of MR antagonists on myocardial I/R injury, as well as post-infarction remodeling. Animal models, predominantly Langendorff technique and left anterior descending coronary artery occlusion (LAD) have confirmed the potency of MRA as preconditioning and postconditioning agents in limiting infarct size and postinfarction remodeling. Several preclinical studies in rodents have established and proved possible mechanisms of cardioprotection by MRA, such as reduction of oxidative stress, reduction of inflammation and apoptosis, therefore limiting infarct zone. However, the results of some clinical trials are inconsistent with these results since they reported no benefit of MRA in acute myocardial infarction. Due to this, further studies and the results of on-going clinical trials regarding MRA administration in patients with acute myocardial infarction are being awaited with great interest.

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“… 11 Several electron-withdrawing groups (in circles) have been tested as direct substituents or on methylene groups at C-2 and C-6 positions ( Scheme 1 , Structure 1 – 6 ), and robust bioactivity was recorded. 12 − 16 …”

Section: Introductionmentioning

confidence: 99%

Highly Efficient Electrocarboxylation Method to Synthesize Novel Acid Derivatives of 1,4-Dihydropyridines and to Study Their Antimicrobial Activity

et al. 2022

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1,4-Dihydropyridines (1,4-DHPs) hold a top-notch position in the pharmaceutical world due to a broader spectrum of applications, whereas the carboxylic moiety has been an integral part of the physiological world, effective food preservatives, and antimicrobial agents. Seeking the enormous potential and applications of these two classes, we worked to combine these to synthesize 2,2′-[3,5-bis(ethoxycarbonyl)-4-phenyl-1,4-dihydropyridine-2,6-diyl]diacetic acid the novel dicarboxylic derivatives of 1,4-DHP ( 9a – k ) achieved via the electro-carboxylation of tetrasubstituted-1,4-dihydropyridines ( 8a – k ) derivatives using Mg–Pt electrodes in an undivided cell. The targeted compounds were established by 1 H, 13 C NMR, IR, and ESI-MS. Further, the synthesized compounds show excellent resistance against various microbes and the activity increased 2–3 folds after the introduction of acid groups. Compound 9b (against E. coli , S. aureus , B. subtilis , A. niger , and P. glabrum ), 9d (against E. coli , K. pneumonia , S. aureus , A. janus , and F. oxysporum) , 9f (against E. coli and P. fluorescens ), and 9k (against F. oxysporum and P. glabrum) were found to be highly active at 4 μg/mL with reference to standard amoxicillin and fluconazole. Further, the present synthetic protocol would open new gates for other researchers to develop new molecules by bioisosteres of these substrates.

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Mineralocorticoid Receptor Antagonists

Cited by 6 publications

References 58 publications

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

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

The role of aldosterone inhibitors in cardiac ischemia–reperfusion injury

Highly Efficient Electrocarboxylation Method to Synthesize Novel Acid Derivatives of 1,4-Dihydropyridines and to Study Their Antimicrobial Activity

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