Abstract
A series of compounds were designed as T-type calcium channel blocker containing 6 or 5 pharmacophore features from structure-based virtual screening. To optimize the suggested structure, over 130 derivatives were synthesized and their inhibitory activities on T-type calcium channel were assayed using in vitro screening system with alpha1(G) and alpha1(H) clones. For the compounds with higher activities in FDSS assay system, the efficacy was measured by patch-clamp method. Among the library with 5 features, alkaneamide derivatives (7b, 9j, 11b, 11g, 11h) with 4-arylsubstituted piperazine showed better IC(50) values than Mibefradil.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alkanes / chemistry*
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Amides / chemical synthesis
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Amides / chemistry
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Amides / pharmacology*
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Animals
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Calcium / metabolism
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Calcium Channel Blockers / chemical synthesis
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Calcium Channel Blockers / chemistry
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Calcium Channel Blockers / pharmacology*
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Calcium Channels, T-Type / drug effects*
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Cells, Cultured / drug effects
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Drug Design
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Inhibitory Concentration 50
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Kidney / drug effects
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Mibefradil / chemical synthesis
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Mibefradil / chemistry
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Mibefradil / pharmacology*
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Models, Chemical
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Molecular Structure
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Oocytes / drug effects
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Piperazines / chemistry
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Stereoisomerism
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Structure-Activity Relationship
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Xenopus laevis
Substances
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Alkanes
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Amides
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Calcium Channel Blockers
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Calcium Channels, T-Type
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Piperazines
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Mibefradil
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Calcium