Mineralocorticoid receptor antagonists: Identification of heterocyclic amide replacements in the oxazolidinedione series

Cox, Jason M.; Chu, Hong D.; Yang, Cangming; Shen, Hong C.; Wu, Zhicai; Balsells, Jaume; Crespo, Alejandro; Brown, Patricia; Zamlynny, Beata; Wiltsie, Judyann; Clemas, Joseph; Gibson, Jonathan; Contino, Lisa C.; Lisnock, JeanMarie; Zhou, Gaochao; García‐Calvo, Margarita; Bateman, Thomas J.; Xu, Ling; Tong, Xinchun; Crook, Martin F.; Sinclair, Peter J.

doi:10.1016/j.bmcl.2014.02.057

Cited by 25 publications

(13 citation statements)

References 29 publications

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“…Oxazolidine-2,4-diones are important structural motifs frequently found in medicinally relevant and biologically active molecules. [1][2][3][4][5] These compounds have been identified as having diverse properties such as antitumor, 1 cardiotonic, 2 antidiabetic, 3 and anti-inflammatory activity. 4 For example, vinzolidine shows broad inhibitory activity against many cancer cell lines.…”

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confidence: 99%

Synthesis of oxazolidine-2,4-diones by a tandem phosphorus-mediated carboxylative condensation–cyclization reaction using atmospheric carbon dioxide

et al. 2015

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The oxazolidine-2,4-dione motif is found frequently in biologically important compounds. A tandem phosphorus-mediated carboxylative condensation of primary amines and α-ketoesters/base-catalyzed cyclization reaction have been developed. These processes provide a novel and convenient access to various oxazolidine-2,4-diones in a one-pot fashion using atmospheric carbon dioxide and readily available substrates under very mild and transition-metal-free conditions.

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confidence: 99%

Synthesis of oxazolidine-2,4-diones by a tandem phosphorus-mediated carboxylative condensation–cyclization reaction using atmospheric carbon dioxide

et al. 2015

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“…Additionally, starting from an HTS, Merck identified a series of MR antagonists based on the oxazolidine-2,4-dione scaffold. Several derivatives showed potent MR affinity, as compound 5 (Figure 1), which has significant selectivity versus other NHRs (IC 50 , PR, AR, GR > 5 μm) [26].…”

Section: Nonsteroidal Mr Ligandsmentioning

confidence: 99%

Advances in the Development of Non-steroidal Mineralocorticoid-receptor Antagonists

Pérez-Gordillo¹,

Vega²,

Gerona‐Navarro³

et al. 2019

Aldosterone-Mineralocorticoid Receptor - Cell Biology to Translational Medicine

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The mineralocorticoid receptor (MR) belongs to the nuclear receptor superfamily and regulates body fluid and electrolyte balance. In the last years, much effort has been put into the development of non-steroidal MR antagonists that overcome the side effects of the marketed steroid drugs, and can be used for the treatment of hypertension and heart failure, among others. Initially, MR was identified in epithelial cells, however it also plays important roles in non-epithelial tissues. In this sense, it is of interest to discover ligands that might induce different MR conformational changes, leading to specific coregulator interactions, which could confer tissue-specific effects. Different series of non-steroidal ligands with diverse central scaffolds has been described, which shows antihypertensive and cardiorenal protective effects. This review covers a description of different non-steroidal MR antagonist families, with special focus on compounds under clinical development. The analysis of the three-dimensional (3D) structures of non-steroidal MR antagonists in complex with the MR ligand-binding domain (LBD), recently reported, highlights the interactions crucial for binding. The structure-activity relationships of known ligands, together with the insights provided by the 3D structures of ligand-LBD MR complexes, could help in the development of non-steroidal MR antagonists with improved properties.

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“…While these studies have been closed (www.clinicaltrials.gov) data has yet to be published. Oxazolidinedione derivative MR antagonists are being developed and studied at the Merck Research Laboratories, but as yet published information is limited to interesting preclinical studies 156–158 .…”

Section: Other Potential Mr Antagonistsmentioning

confidence: 99%

Third-generation Mineralocorticoid Receptor Antagonists

Gómez-Sánchez

2016

Journal of Cardiovascular Pharmacology

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The first mineralocorticoid receptor (MR) antagonist, spironolactone, was developed almost 60 years ago to treat primary aldosteronism and pathological edema. Its use waned in part due to its lack of selectivity. Subsequently knowledge of the scope of MR function was expanded along with clinical evidence of the therapeutic importance of MR antagonists to prevent the ravages of inappropriate MR activation. Forty-two years elapsed between the first and MR-selective second generation of MR antagonists. Fifteen years later, despite serious shortcomings of the existing antagonists, a third generation antagonist has yet to be marketed. Progress has been slowed by the lack of appreciation of the large variety of cell types that express the MR and its diverse cell-type-specific actions, as well as its uniquely complex interactions actions at the molecular level. New MR antagonists should preferentially target the inflammatory and fibrotic effects of MR and perhaps its excitatory effects on sympathetic nervous system, but not the renal tubular epithelium or neurons of the cortex and hippocampus. This review briefly describes efforts to develop a third generation MR antagonist and why fourth generation antagonists and selective agonists based on structural determinants of tissue and ligand-specific MR activation should be contemplated.

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Mineralocorticoid receptor antagonists: Identification of heterocyclic amide replacements in the oxazolidinedione series

Cited by 25 publications

References 29 publications

Synthesis of oxazolidine-2,4-diones by a tandem phosphorus-mediated carboxylative condensation–cyclization reaction using atmospheric carbon dioxide

Synthesis of oxazolidine-2,4-diones by a tandem phosphorus-mediated carboxylative condensation–cyclization reaction using atmospheric carbon dioxide

Advances in the Development of Non-steroidal Mineralocorticoid-receptor Antagonists

Third-generation Mineralocorticoid Receptor Antagonists

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