Endothelin Receptor Antagonists: An Overview of Their Synthesis and Structure-Activity Relationship

Iqbal, Javed; Sanghi, Rashmi; Das, Saibal Kumar

doi:10.2174/1389557053544010

Cited by 22 publications

(11 citation statements)

References 71 publications

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“…It is possible to argue that in vivo administration of inhibitors of ET receptors, L-type Ca 2ϩ channels, and calcineurin prevents CH-induced vasoconstriction and increases in pulmonary pressure since the effectiveness of these drugs in lowering pulmonary pressure in rodents and humans has been previously demonstrated, and the site of action is primarily the vasculature (10,17,18,21,22,44,51,75,82). Elevated intrapulmonary pressure could be a mechanical stimulus that contributes to increased PASMC [Ca 2ϩ ] i leading to NFATc3 activation (36,58).…”

Section: Ch-induced Nfatc3 Activation Requires Et-1 and Rokmentioning

confidence: 99%

Endothelin-1 contributes to increased NFATc3 activation by chronic hypoxia in pulmonary arteries

Garcı́a

Diaz

Nitta

et al. 2011

American Journal of Physiology-Cell Physiology

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Chronic hypoxia (CH) activates the Ca(2+)-dependent transcription factor nuclear factor of activated T cells isoform c3 (NFATc3) in mouse pulmonary arteries. However, the mechanism of this response has not been explored. Since we have demonstrated that NFATc3 is required for CH-induced pulmonary arterial remodeling, establishing how CH activates NFATc3 is physiologically significant. The goal of this study was to test the hypothesis that endothelin-1 (ET-1) contributes to CH-induced NFATc3 activation. We propose that this mechanism requires increased pulmonary arterial smooth muscle cell (PASMC) intracellular Ca(2+) concentration ([Ca(2+)](i)) and stimulation of RhoA/Rho kinase (ROK), leading to calcineurin activation and actin cytoskeleton polymerization, respectively. We found that: 1) CH increases pulmonary arterial pre-pro-ET-1 mRNA expression and lung RhoA activity; 2) inhibition of ET receptors, calcineurin, L-type Ca(2+) channels, and ROK blunts CH-induced NFATc3 activation in isolated intrapulmonary arteries from NFAT-luciferase reporter mice; and 3) both ET-1-induced NFATc3 activation in isolated mouse pulmonary arteries ex vivo and ET-1-induced NFATc3-green fluorescence protein nuclear import in human PASMC depend on ROK and actin polymerization. This study suggests that CH increases ET-1 expression, thereby elevating PASMC [Ca(2+)](i) and RhoA/ROK activity. As previously demonstrated, elevated [Ca(2+)](i) is required to activate calcineurin, which dephosphorylates NFATc3, allowing its nuclear import. Here, we demonstrate that ROK increases actin polymerization, thus providing structural support for NFATc3 nuclear transport.

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Section: Ch-induced Nfatc3 Activation Requires Et-1 and Rokmentioning

confidence: 99%

Endothelin-1 contributes to increased NFATc3 activation by chronic hypoxia in pulmonary arteries

Garcı́a

Diaz

Nitta

et al. 2011

American Journal of Physiology-Cell Physiology

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“…The pyrimidinyl benzenesulfonamide, Bosentan (Ro-47-0203, 26) is competitive mixed endothelin competitive antagonist (with K i 4.7nM at ET A on human smooth muscle cells; K i 95nM at ET B on human placenta [60] in [ 125 I]-ET1 affinity assays) and is FDA approved for use in pulmonary arterial hypertension [61]. Further, it has been shown to be experimentally protective in TNBS-induced colitis in rats and protects against endothelial dysfunction during ischaemia/reperfusion in vivo in humans [62,63].…”

Section: Corticotropin Releasing Factor Recep-torsmentioning

confidence: 99%

“…Bosentan is currently undergoing phase III trials in pulmonary hypertension related to immune disorders and digital ulcers in scleroderma. Enrasentan (SB-217242, 27) was rationally designed indane carboxylic acid series using molecular modelling information from the NMR-derived structure of ET-1 [61]. Enrasentan is a potent mixed ET A /ET B antagonist (displacing [ 125 I]-ET1 with K i 1.1 nM hET A ; K i 111 nM hET B [64]), which inhibits airway eosinophilia and hyperresponsiveness in allergic airway inflammation model in mice [65].…”

Section: Corticotropin Releasing Factor Recep-torsmentioning

confidence: 99%

“…They are 21-residue peptides with 2 intramolecular disulphide bridges. Prominently known for with human psoriasis lesions [67][68][69] [70]) of series designed on a 3,3-diphenyl-2-(pyrimidin-2-yloxy)-propionic acid scaffold [61]. This series has antiinflammatory properties in models of ET-1 induced inflammation and cardiomyopathy and pancreatitis [71,72].…”

Section: Endothelin Receptorsmentioning

confidence: 99%

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Nonpeptide Ligands That Target Peptide-Activated GPCRs In Inflammation

Blakeney¹,

Fairlie

2005

CMC

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The focus of this review is on G protein-coupled receptors (GPCRs) for which nonpeptidic ligands are known and have been evaluated for the treatment of inflammatory conditions. GPCRs are the most prevalent class of cell surface proteins in pharmaceutical research today, and GPCR-targeting drugs account for one tenth of worldwide pharmaceutical sales. Of over 800 human GPCRs identified to date, several hundred are activated by peptides/proteins and just over 30 of these have been identified so far as potential therapeutic targets for the treatment of inflammatory diseases. This review highlights those GPCRs and over 60 structurally diverse nonpeptidic compounds that interact with them and display pro- or anti- inflammatory properties. Among these GPCR targets are the receptors for peptides like bradykinin, chemokines, complement anaphylatoxins, corticotropin releasing factor, endothelins, melanocortins, tachykinins, urocortins, as well as the protease activated receptors (PARs). Other peptide activated GPCRs implicated in inflammation, like those that bind angiotensin II, N-formyl peptides, galanin, neuropeptide Y, opioids and oxytocin, are only briefly discussed because there is either less direct association with inflammation or few/no nonpeptidic antiinflammatory ligands known. While it is still very early in the development of antiinflammatory drugs that target GPCRs, there is already a wealth of information supporting their important roles as cellular sentries in inflammatory diseases. New opportunities are emerging to evaluate antiinflammatory activities of potent and selective GPCR-binding ligands, including those being developed for other disease indications. In summary, GPCRs deserve a great deal more attention as potential therapeutic targets in inflammatory diseases.

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“…Many agonists and antagonists of endothelin receptors are described in literature and classified to many classes according to their chemical structure and their selectivity to receptors. Like peptide [1,[33][34][35][36], and non peptide antagonist, the non peptides could be classified to sulfonamides and nonsulfonamides [1,33,35,37,38]. Recently allosteric modulation inhibition of endothelin *Address correspondence to this author at the Department of Pharmaceutical Chemistry, Garyounis University, Benghazi, Libya; Fax: 00218-61-2231520; E-mail: mabuajila@yahoo.ca receptors ET A has been described in literature [39,40].…”

Section: Introductionmentioning

confidence: 99%

Allosteric Inhibition of [125I] ET-1 Binding to ETA Receptors by Aldoxime and Hydroxamic Acid Derivatives

Ahmed¹,

Nencetti²,

Mazzoni³

et al. 2008

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Endothelin-1 (ET-1), a potent vasoconstrictor peptide, exerts its physiological effects by binding and activating specific G protein-coupled receptors, named ET(A) and ET(B). An unique property of ET-1 is its ability to bind almost irreversibly to its receptors. Aspirin and salicylic acid (SA) are allosteric inhibitors of ET-1 binding to ET(A) receptors. Dihalogenated derivatives of SA have been identified as more potent allosteric inhibitors than aspirin. In this study, disubstituted benzohydroxamic acid, benzaldoximes and dihalosalicylic acid dimers were synthesized and tested as inhibitors of [(125)I]ET-1 binding to ET(A) receptors in rat embryonic cardiomyocyte (H9c2 cell) membranes. Some dihalosalicylic acid dimers 2h showed good inhibitory activity, the most active compounds are the hydroxamic acids derived from anthranilic acid. Among these compounds, the 3, 5-diiodo-2-aminobenzohydroxamic acid e compound 2a is three-folds more potent as inhibitor of [(125I)] ET-1 binding to ET(A) receptors than the 3; 5-diiodosalicylic acid reported in literature. Most aryl aldoximes in this study were biologically inactive as inhibitors of [(125I)] ET-1 binding to ET(A) receptors.

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Endothelin Receptor Antagonists: An Overview of Their Synthesis and Structure-Activity Relationship

Cited by 22 publications

References 71 publications

Endothelin-1 contributes to increased NFATc3 activation by chronic hypoxia in pulmonary arteries

Endothelin-1 contributes to increased NFATc3 activation by chronic hypoxia in pulmonary arteries

Nonpeptide Ligands That Target Peptide-Activated GPCRs In Inflammation

Allosteric Inhibition of [125I] ET-1 Binding to ETA Receptors by Aldoxime and Hydroxamic Acid Derivatives

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