Optimisation and validation of a medium-throughput electrophysiology-based hNav1.5 assay using IonWorks™

Harmer, Alex; Abi‐Gerges, Najah; Easter, Alison; Woods, A.; Lawrence, Chris L.; Small, Ben G; Valentin, Jean‐Pierre; Pollard, Chris

doi:10.1016/j.vascn.2007.09.002

Cited by 78 publications

(42 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We next made a series of related amides (24)(25)(26)(27)(28)(29)31) which all demonstrated good selectivity for Na v 1.7 versus Na v 1.5. In the series of amides described, the (S)-3-fluoropyrrolidine 27 exhibited good activity at Na v 1.7 (FRET IC 50 = 0.37 µM, EP IC 50 = 0.48 µM; manual EP IC 50 = 0.57 µM), good selectivity versus Na v 1.5 (>33 µM) and good pharmacokinetic properties (F = 83%; t 1/2 = 1.7 h).…”

Section: Resultsmentioning

confidence: 99%

Substituted Indazoles as Na_v1.7 Blockers for the Treatment of Pain

et al. 2016

View full text Add to dashboard Cite

The genetic validation for the role of the Nav1.7 voltage-gated ion channel in pain signaling pathways makes it an appealing target for the potential development of new pain drugs. The utility of nonselective Nav blockers is often limited due to adverse cardiovascular and CNS side effects. We sought more selective Nav1.7 blockers with oral activity, improved selectivity, and good druglike properties. The work described herein focused on a series of 3- and 4-substituted indazoles. SAR studies of 3-substituted indazoles yielded analog 7 which demonstrated good in vitro and in vivo activity but poor rat pharmacokinetics. Optimization of 4-substituted indazoles yielded two compounds, 27 and 48, that exhibited good in vitro and in vivo activity with improved rat pharmacokinetic profiles. Both 27 and 48 demonstrated robust activity in the acute rat monoiodoacetate-induced osteoarthritis model of pain, and subchronic dosing of 48 showed a shift to a lower EC50 over 7 days.

show abstract

Section: Resultsmentioning

confidence: 99%

Substituted Indazoles as Na_v1.7 Blockers for the Treatment of Pain

et al. 2016

View full text Add to dashboard Cite

show abstract

“…1 The path to new medicines necessitates the screening of large numbers of compounds against ion channel targets, for the purpose of lead generation and for the assessment of, for instance, the cardiac safety liability of a compound. 2,3 Traditionally, the study of ion channels has relied on conventional patch-clamp electrophysiology. This technique yields high-fidelity data but is labor intensive, requires a highly skilled experimenter, and may be used to screen only a small number of compounds.…”

Section: Introductionmentioning

confidence: 99%

Use of Escin as a Perforating Agent on the IonWorks Quattro Automated Electrophysiology Platform

Morton

Main

2013

SLAS Discovery

View full text Add to dashboard Cite

The automated electrophysiology platform IonWorks has facilitated the medium-throughput study of ion channel biology and pharmacology. Electrical and chemical access to the cell is by perforated patch, afforded by amphotericin. Permeation of the amphotericin pore is limited to monovalent cations. We describe here the use of the saponin escin as an alternative perforating agent. With respect to the number and robustness of seals formed across a variety of cell and ion channel types, the performance of escin is equal to that of amphotericin. Escin also permits the permeation of larger molecules through its pore. These include nucleotides, important intracellular modulators of ion channel activity that can be used to prevent ion channel rundown of, for instance, Ca V 1.2. Furthermore, pharmacologic agents such as QX314 can also permeate and be used for mechanistic studies. Escin, in combination with IonWorks, increases the scope of ion channel screening and can facilitate the assay of previously difficult-to-assay targets.

show abstract

“…However, the throughput of conventional electrophysiology assays is too low to meet drug discovery project needs and requires highly trained personnel. Recent developments in automated patch-clamp technologies have enabled high throughput profiling of compounds during early stages of drug discovery (Dunlop et al, 2008; Harmer et al, 2008; Castle et al, 2009; Chen et al, 2009; Cao et al, 2010). Biophysical properties and pharmacological profiles obtained from automated hNav1.5 assays show good concordance with manual patch-clamp recordings (Harmer et al, 2008; Castle et al, 2009; Cao et al, 2010).…”

Section: Pre-clinical Assessmentmentioning

confidence: 99%

“…Recent developments in automated patch-clamp technologies have enabled high throughput profiling of compounds during early stages of drug discovery (Dunlop et al, 2008; Harmer et al, 2008; Castle et al, 2009; Chen et al, 2009; Cao et al, 2010). Biophysical properties and pharmacological profiles obtained from automated hNav1.5 assays show good concordance with manual patch-clamp recordings (Harmer et al, 2008; Castle et al, 2009; Cao et al, 2010). Because many clinically used sodium channel blockers are state-dependent modulators, evaluation of state dependence is an important part of pre-clinical safety risk assessment (Cao et al, 2010).…”

Section: Pre-clinical Assessmentmentioning

confidence: 99%

Cardiac Safety Implications of hNav1.5 Blockade and a Framework for Pre-Clinical Evaluation

Erdemli¹,

Kim²,

Ju³

et al. 2012

Front. Pharmacol.

View full text Add to dashboard Cite

The human cardiac sodium channel (hNav1.5, encoded by the SCN5A gene) is critical for action potential generation and propagation in the heart. Drug-induced sodium channel inhibition decreases the rate of cardiomyocyte depolarization and consequently conduction velocity and can have serious implications for cardiac safety. Genetic mutations in hNav1.5 have also been linked to a number of cardiac diseases. Therefore, off-target hNav1.5 inhibition may be considered a risk marker for a drug candidate. Given the potential safety implications for patients and the costs of late stage drug development, detection, and mitigation of hNav1.5 liabilities early in drug discovery and development becomes important. In this review, we describe a pre-clinical strategy to identify hNav1.5 liabilities that incorporates in vitro, in vivo, and in silico techniques and the application of this information in the integrated risk assessment at different stages of drug discovery and development.

show abstract

Optimisation and validation of a medium-throughput electrophysiology-based hNav1.5 assay using IonWorks™

Cited by 78 publications

References 25 publications

Substituted Indazoles as Na_v1.7 Blockers for the Treatment of Pain

Substituted Indazoles as Na_v1.7 Blockers for the Treatment of Pain

Use of Escin as a Perforating Agent on the IonWorks Quattro Automated Electrophysiology Platform

Cardiac Safety Implications of hNav1.5 Blockade and a Framework for Pre-Clinical Evaluation

Contact Info

Product

Resources

About

Optimisation and validation of a medium-throughput electrophysiology-based hNav1.5 assay using IonWorks™

Cited by 78 publications

References 25 publications

Substituted Indazoles as Nav1.7 Blockers for the Treatment of Pain

Substituted Indazoles as Nav1.7 Blockers for the Treatment of Pain

Use of Escin as a Perforating Agent on the IonWorks Quattro Automated Electrophysiology Platform

Cardiac Safety Implications of hNav1.5 Blockade and a Framework for Pre-Clinical Evaluation

Contact Info

Product

Resources

About

Substituted Indazoles as Na_v1.7 Blockers for the Treatment of Pain

Substituted Indazoles as Na_v1.7 Blockers for the Treatment of Pain