"目录号: HY-14183
Membrane Transporter/Ion Channel-
Vernakalant hydrochloride 是一种混合电压和频率依赖性的Na+和K+通道阻断剂。Vernakalant 抑制Kv1.5 channelwt，Kv1.5 channelI508F，Kv1.5 channelT479A，IC50分别为 13.35±0.93 μM
Potassium Channel
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生物活性
Description
Vernakalant hydrochloride is a mixed voltage- and frequency-dependentNa+and atria-preferredK+channelblocker.IC50for block by Vernakalant of wild-type and mutant Kv1.5 channels Fractional block is 13.35±0.93 μM, 0.61±0.03 μM, and 1.63±0.09 μM forKv1.5 channelwt,Kv1.5 channelI508F,Kv1.5 channelT479A, respectively.
IC50& Target
IC50: 13.35±0.93 μM (Kv1.5 channelwt), 0.61±0.03 μM (I508F), 1.63±0.09 μM (Kv1.5 channelT479A)[1]
In Vitro
Block of Kv1.5 by Vernakalant Hydrochloride is mediated after channel activation, because Vernakalant causes a relatively rapid onset of block of channel current upon depolarization but little evidence of resting or “tonic” block of the channel. In the presence of 10 μM Vernakalant, rapid block is apparent after channel opening, and a steady-state current level is rapidly reached. The most important effect is the reduction in potency for Vernakalant centered at I502A, which had an IC50of 329±19 μM (n=4-10), compared with a control IC50of 13.4±0.9 μM (n=5-23), which is a 25-fold decrease in potency. V505A, I508A, T480A, and C500A showed lesser reductions in potency on Kv1.5, of between 3- and 4-fold. I508Y in our experiments increased the IC50for Vernakalant on Kv1.5 to 24.7 μM, again similar to the reported value for hERG[1].
Clinical Trial
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June 2004
Phase 3
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October 2005
Phase 3
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June 2004
Phase 3
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October 2009
Phase 3
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Maastricht University Medical Center
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August 2012
Phase 4
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Cardiome Pharma-Astellas Pharma US, Inc.
Atrial Flutter
August 2003
Phase 2-Phase 3
NCT00668759
Cardiome Pharma
Atrial Fibrillation
April 2008
Phase 3
NCT00526136
Cardiome Pharma
Atrial Fibrillation
March 2007
Phase 2
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Cardiome Pharma-Astellas Pharma US, Inc.
Atrial Fibrillation
August 2003
Phase 3
NCT01447862
Medical University of Vienna
Atrial Fibrillation
October 2011
Phase 4
NCT01627106
Cardiome Pharma
Atrial Fibrillation
September 2012
Phase 4
NCT01370629
Cardiome Pharma
Atrial Fibrillation
August 2011
NCT00267930
Cardiome Pharma
Atrial Fibrillation
December 2005
Phase 2
NCT01174160
Cardiome Pharma
Atrial Fibrillation
August 2010
Phase 3
NCT03005366
David Filgueiras-Rama-Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III-Hospital San Carlos, Madrid
Paroxysmal Atrial Fibrillation
January 2017
Phase 4
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References
[1].Eldstrom J, et al. The molecular basis of high-affinity binding of the antiarrhythmic compound Vernakalant (RSD1235) to Kv1.5 channels. Mol Pharmacol. 2007 Dec;72(6):1522-34.
[2].Chiba T, et al. Influences of rapid pacing-induced electrical remodeling on pharmacological manipulation of the atrial refractoriness in rabbits. J Pharmacol Sci. 2016 Mar;130(3):170-6.