Abstract
Herein we describe the discovery, optimization, and structure-activity relationships of novel potent pyrrolopyrimidine Na(v)1.7 antagonists. Hit-to-lead SAR studies of the pyrrolopyrimidine core, head, and tail groups of the molecule led to the identification of pyrrolopyrimidine 48 as exceptionally potent Na(v)1.7 blocker with good selectivity over hERG and improved microsomal stability relative to our hit molecule and pyrazolopyrimidine 8 as a promising starting point for future optimization efforts.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Drug Discovery
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Humans
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Microsomes, Liver / metabolism
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NAV1.7 Voltage-Gated Sodium Channel
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Pain / drug therapy
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Pyrimidines / chemistry*
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Pyrimidines / metabolism
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Pyrimidines / pharmacology*
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Pyrroles / chemistry*
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Pyrroles / metabolism
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Pyrroles / pharmacology*
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Sodium Channel Blockers / chemistry*
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Sodium Channel Blockers / metabolism
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Sodium Channel Blockers / pharmacology*
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Sodium Channels / metabolism*
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Structure-Activity Relationship
Substances
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NAV1.7 Voltage-Gated Sodium Channel
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Pyrimidines
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Pyrroles
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SCN9A protein, human
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Sodium Channel Blockers
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Sodium Channels
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pyrrolopyrimidine