Abstract
A novel series of pyrrolidine derivatives as Na(+) channel blockers was synthesized and evaluated for their inhibitory effects on neuronal Na(+) channels. Structure-activity relationship (SAR) studies of a pyrrolidine analogue 2 led to the discovery of 5e as a potent Na(+) channel blocker with a low inhibitory action against human ether-a-go-go-related gene (hERG) channels. Compound 5e showed remarkably neuroprotective activity in a rat transient middle cerebral artery occlusion (MCAO) model, suggesting that 5e would act as a neuroprotectant for ischemic stroke.
Copyright © 2013 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Disease Models, Animal
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Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
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Ether-A-Go-Go Potassium Channels / metabolism
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Humans
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Infarction, Middle Cerebral Artery / drug therapy
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Neurons / drug effects
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Neurons / metabolism
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Neuroprotective Agents / chemical synthesis
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Neuroprotective Agents / pharmacology
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Neuroprotective Agents / therapeutic use
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Pyrrolidines / chemistry*
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Pyrrolidines / pharmacology
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Pyrrolidines / therapeutic use
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Rats
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Sodium Channel Blockers / chemical synthesis*
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Sodium Channel Blockers / pharmacology
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Sodium Channel Blockers / therapeutic use
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Stroke / drug therapy*
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Structure-Activity Relationship
Substances
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Ether-A-Go-Go Potassium Channels
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Neuroprotective Agents
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Pyrrolidines
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Sodium Channel Blockers