Abstract
Optimization of the novel alpha-2-delta-1 ligand 4 provided compounds 37 and 38 which have improved DMPK profiles, good in vivo analgesic activity and in vitro selectivity over alpha-2-delta-2. An in-house P-gp prediction programme and the MetaSite software package were used to help solve the specific problems of high P-gp efflux and high in vivo clearance.
Copyright 2010 Elsevier Ltd. All rights reserved.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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Analgesics / chemical synthesis
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Analgesics / chemistry*
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Analgesics / therapeutic use
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Animals
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Calcium Channel Blockers / chemical synthesis
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Calcium Channel Blockers / chemistry*
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Calcium Channel Blockers / therapeutic use
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Calcium Channels / chemistry*
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Calcium Channels / metabolism
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Calcium Channels, L-Type
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Ligands
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Neuralgia / drug therapy*
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Pyrazoles / chemical synthesis
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Pyrazoles / chemistry*
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Pyridazines / chemical synthesis
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Pyridazines / chemistry*
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Pyridazines / therapeutic use
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Pyridines / chemical synthesis
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Pyridines / chemistry*
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Rats
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Structure-Activity Relationship
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Analgesics
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Cacna2d1 protein, rat
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Calcium Channel Blockers
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Calcium Channels
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Calcium Channels, L-Type
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Ligands
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Pyrazoles
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Pyridazines
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Pyridines
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pyrazolopyridine
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pyridazine