Effects of phosphodiesterase (PDE) inhibitors on human ether‐a‐go‐go related gene (hERG) channel activity

Yunomae, Kiyokazu; Ichisaki, Satoko; Matsuo, Junko; Nagayama, Shin; Fukuzaki, Koichiro; Nagata, Ryoichi; Kito, Go

doi:10.1002/jat.1201

Cited by 9 publications

(9 citation statements)

References 27 publications

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“…The same problem can be seen with the vinpocetine molecule. An IC 50 of 32 nm was considered in our study, whereas recently an IC 50 of 130 nm was reported . Clearly, the introduction of uncertainty in the biological activity reduces the performance of the model, and we expected to get a poor predictive model with weak correlation between GRIND descriptors and the activity.…”

Section: Resultsmentioning

confidence: 94%

hERG Classification Model Based on a Combination of Support Vector Machine Method and GRIND Descriptors

et al. 2008

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The human Ether-a-go-go Related Gene (hERG) potassium channel is one of the major critical factors associated with QT interval prolongation and development of arrhythmia called Torsades de Pointes (TdP). It has become a growing concern of both regulatory agencies and pharmaceutical industries who invest substantial effort in the assessment of cardiac toxicity of drugs. The development of in silico tools to filter out potential hERG channel inhibitors in early stages of the drug discovery process is of considerable interest. Here, we describe binary classification models based on a large and diverse library of 495 compounds. The models combine pharmacophore-based GRIND descriptors with a support vector machine (SVM) classifier in order to discriminate between hERG blockers and nonblockers. Our models were applied at different thresholds from 1 to 40 microm and achieved an overall accuracy up to 94% with a Matthews coefficient correlation (MCC) of 0.86 ( F-measure of 0.90 for blockers and 0.95 for nonblockers). The model at a 40 microm threshold showed the best performance and was validated internally (MCC of 0.40 and F-measure of 0.57 for blockers and 0.81 for nonblockers, using a leave-one-out cross-validation). On an external set of 66 compounds, 72% of the set was correctly predicted ( F-measure of 0.86 and 0.34 for blockers and nonblockers, respectively). Finally, the model was also tested on a large set of hERG bioassay data recently made publicly available on PubChem ( http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?aid=376) to achieve about 73% accuracy ( F-measure of 0.30 and 0.83 for blockers and nonblockers, respectively). Even if there is still some limitation in the assessment of hERG blockers, the performance of our model shows an improvement between 10% and 20% in the prediction of blockers compared to other methods, which can be useful in the filtering of potential hERG channel inhibitors.

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Section: Resultsmentioning

confidence: 94%

hERG Classification Model Based on a Combination of Support Vector Machine Method and GRIND Descriptors

et al. 2008

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“…Moreover, PDE5 inhibitors have already been reported to have a concentration-dependent inhibitory effect on Ikr and prolongation of cardiac repolarization 29 . Interestingly, most PDE inhibitors decreases hERG current directly or indirectly while two PDE3 inhibitors (amrinone and milrinone) fail to exhibit any hERG inhibitory effects 30 . In this study, amrinone did not inhibit Ikr current in the control and HF myocytes, consistent with previous reports 30 .…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, most PDE inhibitors decreases hERG current directly or indirectly while two PDE3 inhibitors (amrinone and milrinone) fail to exhibit any hERG inhibitory effects 30 . In this study, amrinone did not inhibit Ikr current in the control and HF myocytes, consistent with previous reports 30 . However, our studies further showed that Ikr currents were inhibited by salbutamol after pretreatment with PDE3 inhibitor, and APD was prolonged more.…”

Section: Discussionmentioning

confidence: 99%

β2 adrenergic receptor activation governs cardiac repolarization and arrhythmogenesis in a guinea pig model of heart failure

Wang

Yuan

Zhang

et al. 2015

Sci Rep

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β2-AR activation increases the risk of sudden cardiac death (SCD) in heart failure (HF) patients. Non-selective β-AR blockers have greater benefits on survival than selective β1-AR blockers in chronic HF patients, indicating that β2-AR activation contributes to SCD in HF. This study investigated the role of β2-AR activation on repolarization and ventricular arrhythmia (VA) in the experimental HF model. The guinea pig HF was induced by descending aortic banding. The effective refractoriness period (ERP), corrected QT (QTc) and the incidence of VA were examined using Langendorff and programmed electrical stimulation. Ikr and APD were recorded by the whole cell patch clamp. Selective β2-AR agonist salbutamol significantly increased the incidence of VA, prolonged QTc and shortened ERP. These effects could be prevented by the selective β2-AR antagonist, ICI118551. Salbutamol prolonged APD90 and reduced Ikr in guinea pig HF myocytes. The antagonists of cAMP (Rp-cAMP) and PKA (KT5720) attenuated Ikr inhibition and APD prolongation induced by salbutamol. However, the antagonists of Gi protein (PTX) and PDE III (amrinone) showed opposite effects. This study indicates that β2-AR activation increases the incidence of VA in the experimental HF model via activation of Gs/cAMP/PKA and/or inhibition of Gi/PDE pathways.

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“…PPB are either from published data (plain text) or measured in our laboratories (bold italics). [22]; c: [23]; d: [24,25]; e: [26]; f: [27]; g: [28]; h: [19]; i: [29]; j: [30]; k: [31]; l: [32]; m: [33]; n: [34]; o: [35]; p: [36]; q: [37]; r: [38]; s: [39]; t: [40]; u: [41]; v: [42]; w: [43]; x: [44]; y: [45]; z: [46]; aa: [47]; bb: [48]; cc: [49]; dd: [50]; ee: [51]; ff: [52]; gg: [53]; hh: [54]; ii: [55]; jj: [56]; kk: [57]; ll: [58]; mm: [59]; nn: [60]; oo: [61]; pp: [62]; qq: [63]; rr: [64]; ss: [65]; tt: [66]; uu: [67]; vv: [68]; ww: …”

Section: Drugs With a Cardiovascular Target Without A Direct Role In mentioning

confidence: 99%

Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells: An In-Vitro Model to Predict Cardiac Effects of Drugs

Sube¹,

Ertel²

2017

JBiSE

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Introduction: Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CM) form spontaneously beating syncytia in-vitro. We evaluated whether hiPSC-CM are a compelling model of human cardiac pharmacology useful for early drug development. Methods: We measured hiPSC-CM beating frequency using Ca-sensitive dyes and a high-throughput screening system. We quantified the effects of 640 drugs with various structures and pharmacologies. Results: When tested at 1 µM, most drugs without direct effects on heart rhythm or with effects at high concentrations do not change frequency, indicating specificity. In contrast, the preparation detects compounds with direct activity on heart rhythm, demonstrating sensitivity. In particular, β-adrenergic agonists increase frequency and the model differentiates β2 from β1 agonists, as well as partial from full agonists. Phosphodiesterase inhibitors have subtype-specific actions and PDE4 is particularly important in controlling frequency. The preparation is sensitive to cardiac ion channel blockers: L-type calcium channel blockers, Class-I and Class-III antiarrhythmics change frequency but drugs acting on K ATP channels do not. The assay detects compounds blocking the cardiac rapid delayed-rectifier K channel and is an alternative to the classic "hERG test".Conclusion: hiPSC-CM are a useful in-vitro cardiac model in drug development since they respond appropriately to drugs that modify heart rate in humans.

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Effects of phosphodiesterase (PDE) inhibitors on human ether‐a‐go‐go related gene (hERG) channel activity

Cited by 9 publications

References 27 publications

hERG Classification Model Based on a Combination of Support Vector Machine Method and GRIND Descriptors

hERG Classification Model Based on a Combination of Support Vector Machine Method and GRIND Descriptors

β2 adrenergic receptor activation governs cardiac repolarization and arrhythmogenesis in a guinea pig model of heart failure

Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells: An In-Vitro Model to Predict Cardiac Effects of Drugs

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