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Potassium(1+) inhibits KCNH2. 18 / 19
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"Furthermore, to address hERG potassium ion channel inhibition, a known limitation in S1R drug development, we evaluated compound 19's cardiotoxicity potential."
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"As first reported by Guo and colleagues, low-extracellular potassium causes degradation of the 155 kD form of HERG through an endocytic mechanism involving mono-ubiquitination."
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"The other exciting feature of adding methyl group at the R 5 position was the elimination of hERG K+ channel inhibition ( 7 vs 3a and 37 vs 3v ), which was observed in early analogs ( 3a and 3v ) and was a major liability for the cores having a bridgehead nitrogen atom, such as imidazo[1,2- a ]pyridine ( 3a and 3v ), 1,2,4-triazolo[4,3- a ]pyridine ( 34 ) and imidazo[1,2- a ]pyrimidine ( 31 )."
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"The lack of hERG K+ channel inhibition for a number of tested compounds suggests favorable potential for cardiac safety."
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"The hERG potassium current inhibition showed minimal effect in HEK293 cells at ~100‐fold higher concentrations than achieved in adult patients."
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"Prioritized analogs exhibiting EC 50 s ≤ 4 nM against all tested pseudotyped viruses and having optimal MLM metabolic stability profiles, as well as a lack of hERG K+ channel inhibition ( 7 , 35 , 37 , 38 , 39 , and 40 ), were selected for further advancement and evaluated for efficacy in replicative LASV plaque assay and LASV and JUNV viral yield reduction (VYR) assays ( xref )."
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"Secondly, low extracellular potassium can also increase the blockade of hERG currents by drugs [XREF_BIBR, XREF_BIBR]."
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"AM-2-19 showed no evidence of human ether-a-go-go related gene (hERG) potassium current inhibition, genotoxicity or drug–drug interactions ( xref and xref )."
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"Elevation of extracellular potassium decreases inactivation of Kv11.1 channels resulting in increased current amplitude at steady-state conditions ( 23 )."
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"This ion channel plays an important role in the repolarization phase of the cardiac action potential by mediating the rapid component of cardiac delayed rectifier K+ current.31,32 The most common mechanism of drug-induced QT prolongation is due to hERG inhibition.33,34 Several antitubercular agents and repurposed COVID-19 drugs have been reported to inhibit hERG and result in QT interval prolongation.35–38 Hence, there is an increased potential for DDIs due to QT prolongation."
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"Reaction co-ordinate diagrams for hERG inactivation A, Illustration of how REFER analysis can be applied to hERG K+ channel inactivation."
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"We have addressed whether some of the beta-adrenoceptor blockers commonly used to prevent the development of these arrhythmias could per se block the cardiac HERG (Human Ether-a-go-go-Related Gene) potassium channels, which would be a most unwanted side effect."
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"14 This benchmark compound exhibited excellent binding activity (IC 50 = 0.8 nM) and acceptable rat PK profile (rat AUC = 5.1 μM h), but showed undesirable hERG K+ channel inhibition (>90% inhibition [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"The hERG potassium ion channel inhibition and analysis of this process is the basis in pharmacological safety research of new drugs beceause inhibition of this channel may lead for example to arrhythmia, which may occasionally have fatal results due to subsequent ventricular fibrillation [ xref ]."
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"Inhibition of depolarization induced [3H] noradrenaline release from SH-SY5Y human neuroblastoma cells by some second generation H1 receptor antagonists through blockade of store operated Ca2+ channels (SOCs) 11Abbreviations : hERG, human Ether-a-go-go Related Gene; SOC, Ca2+ currents activated by [Ca2+] i store depletion; NE, norepinephrine; [K+] e, e xtracellular K+ concentration; [Ca2+] i, intracellular Ca2+ concentration; HBS, HEPES buffered saline; SERCA, sarcoplasmic-endoplasmic reticulum calcium ATPase; and TTX, tetrodotoxin."
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"These results demonstrate that [K+] o does not directly modulate drug block of hERG channels expressed in an HEK-293 cell line."
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"HERG Potassium Channel Inhibition."
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"Our device was also tested for its response with E-4031, which is a potassium ion channel blocker of the HERG channel and is known to cause prolongation of QT interval without any effect on contraction force."
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