Abstract
Recent findings showing a relation between mutations in the Na(V)1.7 channel in humans and altered pain sensation has contributed to increase the attractiveness of this ion channel as target for development of potential analgesics. Amido chromanes 1 and 2 were identified as blockers of the Na(V)1.7 channel and analogues with modifications of the 5-substituent and the carboxamide part of the molecule were prepared to establish the structure-activity relationship. Compounds 13 and 29 with good overall in vitro and in vivo rat PK profile were identified. Furthermore, 29 showed in vivo efficacy in a nociceptive pain model.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Analgesics / chemistry
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Analgesics / pharmacokinetics
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Analgesics / pharmacology
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Analgesics / therapeutic use
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Animals
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Chromans / chemistry*
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Chromans / pharmacokinetics
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Chromans / pharmacology
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Chromans / therapeutic use*
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Formaldehyde
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Humans
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NAV1.7 Voltage-Gated Sodium Channel / metabolism*
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Nociceptive Pain / chemically induced
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Nociceptive Pain / drug therapy*
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Rats
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Structure-Activity Relationship
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Voltage-Gated Sodium Channel Blockers / chemistry
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Voltage-Gated Sodium Channel Blockers / pharmacokinetics
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Voltage-Gated Sodium Channel Blockers / pharmacology*
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Voltage-Gated Sodium Channel Blockers / therapeutic use*
Substances
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Analgesics
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Chromans
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NAV1.7 Voltage-Gated Sodium Channel
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Voltage-Gated Sodium Channel Blockers
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Formaldehyde