Abstract
The discovery of a series of 5-HT4 receptor agonists based on a novel 2-alkylbenzimidazole aromatic core is described. Optimization of the 2-substituent of the benzimidazole ring led to a series of agonists with subnanomolar binding affinity and moderate-to-high intrinsic activity relative to that of 5-HT. Consistent with our previously described multivalent design approach to this target, subsequent optimization of the linker and secondary binding group regions of the series afforded compound 18 (TD-8954), a potent and selective 5-HT4 receptor agonist in vitro with demonstrated prokinetic activity in multiple species.
Copyright © 2013 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Benzimidazoles / chemical synthesis
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Benzimidazoles / chemistry*
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Benzimidazoles / pharmacokinetics
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Crystallography, X-Ray
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Dogs
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Drug Evaluation, Preclinical
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Guinea Pigs
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Half-Life
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Intestinal Mucosa / metabolism
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Male
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Molecular Conformation
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Piperidines / chemical synthesis
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Piperidines / chemistry*
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Piperidines / pharmacokinetics
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Protein Isoforms / antagonists & inhibitors
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Protein Isoforms / metabolism
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Rats
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Rats, Sprague-Dawley
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Receptors, Serotonin, 5-HT4 / chemistry*
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Receptors, Serotonin, 5-HT4 / metabolism
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Serotonin 5-HT4 Receptor Agonists / chemical synthesis
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Serotonin 5-HT4 Receptor Agonists / chemistry*
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Serotonin 5-HT4 Receptor Agonists / pharmacokinetics
Substances
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4-((4-((2-isopropyl-1H-benzoimidazole-4-carbonyl)amino)methyl)piperidin-1-ylmethyl)piperidine-1-carboxylic acid methyl ester
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Benzimidazoles
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Piperidines
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Protein Isoforms
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Serotonin 5-HT4 Receptor Agonists
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Receptors, Serotonin, 5-HT4
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benzimidazole