Discovery of 6-[5-(4-fluorophenyl)-3-methyl-pyrazol-4-yl]-benzoxazin-3-one derivatives as novel selective nonsteroidal mineralocorticoid receptor antagonists

Hasui, Tomoaki; Ohyabu, Norio; Ohra, Taiichi; Fuji, Koji; Sugimoto, Takafumi; Fujimoto, Jun; Asano, Kouhei; Oosawa, Masato; Shiotani, S; Nishigaki, Nobuhiro; Kusumoto, Keiji; Matsui, Hideki; Mizukami, Atsushi; Habuka, Noriyuki; Sogabe, Satoshi; Endo, Satoshi; Ono, Midori; Siedem, Christopher S.; Tang, Tony P.; Gauthier, Cassandra; Meese, Lisa A. De; Boyd, Steven A.; Fukumoto, Shoji

doi:10.1016/j.bmc.2014.07.038

Cited by 27 publications

(16 citation statements)

References 22 publications

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“…The MIF of 4PF3_2 (Fig. 3) is measured in the substrate binding-site where the compound 6-[1-(2,2-difluoro-3-hydroxypropyl)-5-(4-fluorophenyl)-3-methyl-1 H -pyrazol-4-yl]-2 H -1,4-benzoxazin-3(4 H )-one is bound in the crystal structure 4PF3 [46]. The MIF contains hydrogen bond donor and acceptor probes as well as hydrophobic and aromatic probes.…”

Section: Resultsmentioning

confidence: 99%

Large-scale detection of drug off-targets: hypotheses for drug repurposing and understanding side-effects

Chartier

Morency

Zylber

et al. 2017

BMC Pharmacol Toxicol

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BackgroundPromiscuity in molecular interactions between small-molecules, including drugs, and proteins is widespread. Such unintended interactions can be exploited to suggest drug repurposing possibilities as well as to identify potential molecular mechanisms responsible for observed side-effects.MethodsWe perform a large-scale analysis to detect binding-site molecular interaction field similarities between the binding-sites of the primary target of 400 drugs against a dataset of 14082 cavities within 7895 different proteins representing a non-redundant dataset of all proteins with known structure. Statistically-significant cases with high levels of similarities represent potential cases where the drugs that bind the original target may in principle bind the suggested off-target. Such cases are further analysed with docking simulations to verify if indeed the drug could, in principle, bind the off-target. Diverse sources of data are integrated to associated potential cross-reactivity targets with side-effects.ResultsWe observe that promiscuous binding-sites tend to display higher levels of hydrophobic and aromatic similarities. Focusing on the most statistically significant similarities (Z-score ≥ 3.0) and corroborating docking results (RMSD < 2.0 Å), we find 2923 cases involving 140 unique drugs and 1216 unique potential cross-reactivity protein targets. We highlight a few cases with a potential for drug repurposing (acetazolamide as a chorismate pyruvate lyase inhibitor, raloxifene as a bacterial quorum sensing inhibitor) as well as to explain the side-effects of zanamivir and captopril. A web-interface permits to explore the detected similarities for each of the 400 binding-sites of the primary drug targets and visualise them for the most statistically significant cases.ConclusionsThe detection of molecular interaction field similarities provide the opportunity to suggest drug repurposing opportunities as well as to identify potential molecular mechanisms responsible for side-effects. All methods utilized are freely available and can be readily applied to new query binding-sites. All data is freely available and represents an invaluable source to identify further candidates for repurposing and suggest potential mechanisms responsible for side-effects.Electronic supplementary materialThe online version of this article (doi:10.1186/s40360-017-0128-7) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Large-scale detection of drug off-targets: hypotheses for drug repurposing and understanding side-effects

Chartier

Morency

Zylber

et al. 2017

BMC Pharmacol Toxicol

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“…Molecular Modeling and MD Simulations. Models of native hMR and hMR-T870L LBD were generated using the MODELER software (version 9.14) (26); the X-ray crystal structure of hMR with the highest resolution (PDB ID code: 4PF3) was used as the template for these models (27) as detailed in SI Appendix.…”

Section: Methodsmentioning

confidence: 99%

Molecular evolution of the switch for progesterone and spironolactone from mineralocorticoid receptor agonist to antagonist

Fuller

Yao

Jin

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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The mineralocorticoid receptor (MR) is highly conserved across vertebrate evolution. In terrestrial vertebrates, the MR mediates sodium homeostasis by aldosterone and also acts as a receptor for cortisol. Although the MR is present in fish, they lack aldosterone. The MR binds progesterone and spironolactone as antagonists in human MR but as agonists in zebrafish MR. We have defined the molecular basis of these divergent responses using MR chimeras between the zebrafish and human MR coupled with reciprocal site-directed mutagenesis and molecular dynamic (MD) simulation based on the crystal structures of the MR ligand-binding domain. Substitution of a leucine by threonine in helix 8 of the ligand-binding domain of the zebrafish MR confers the antagonist response. This leucine is conserved across fish species, whereas threonine (serine in rodents) is conserved in terrestrial vertebrate MR. MD identified an interaction of the leucine in helix 8 with a highly conserved leucine in helix 1 that stabilizes the agonist conformation including the interaction between helices 3 and 5, an interaction which has previously been characterized. This switch in the MR coincides with the evolution of terrestrial vertebrates and of aldosterone synthesis. It was perhaps mandatory if the appearance of aldosterone as a specific mediator of the homeostatic salt retention was to be tolerated. The conformational changes also provide insights into the structural basis of agonism versus antagonism in steroid receptors with potential implications for drug design in this important therapeutic target.

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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%

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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Discovery of 6-[5-(4-fluorophenyl)-3-methyl-pyrazol-4-yl]-benzoxazin-3-one derivatives as novel selective nonsteroidal mineralocorticoid receptor antagonists

Cited by 27 publications

References 22 publications

Large-scale detection of drug off-targets: hypotheses for drug repurposing and understanding side-effects

Large-scale detection of drug off-targets: hypotheses for drug repurposing and understanding side-effects

Molecular evolution of the switch for progesterone and spironolactone from mineralocorticoid receptor agonist to antagonist

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

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