Abstract
Further application of our multivalent approach to drug discovery directed to 5-HT(4) receptor agonists is described. Optimization of the linker and secondary binding amine in the indazole-tropane primary binding group series, for binding affinity and functional potency at the 5-HT(4) receptor, selectivity over the 5-HT(3) receptor, oral pharmacokinetics, and in vivo efficacy in models of GI motility, resulted in the identification of clinical compound TD-2749.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Administration, Oral
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Animals
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Cell Line
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Drug Discovery
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Heterocyclic Compounds / administration & dosage
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Heterocyclic Compounds / chemistry*
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Heterocyclic Compounds / pharmacokinetics
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Humans
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Male
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Molecular Structure
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Organ Specificity
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Piperazines / administration & dosage
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Piperazines / chemistry*
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Piperazines / pharmacokinetics
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Rats
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Rats, Sprague-Dawley
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Serotonin 5-HT4 Receptor Agonists / administration & dosage
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Serotonin 5-HT4 Receptor Agonists / chemistry*
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Serotonin 5-HT4 Receptor Agonists / pharmacokinetics
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Structure-Activity Relationship
Substances
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Heterocyclic Compounds
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Piperazines
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Serotonin 5-HT4 Receptor Agonists
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TD-2749