Abstract
Optimization of our HTS hit 1, mainly focused on modification at the C-2 position of the benzimidazole core, is described. Elimination of the flexible and metabolically labile -S-CH(2)- part and utilization of less lipophilic pyridone substructure led to identification of novel NPY Y5 receptor antagonists 6, which have low to sub-nanomolar Y5 receptor binding affinity with improved CYP450 inhibition profiles, good solubilities and high metabolic stabilities.
Copyright © 2012 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 / metabolism
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Benzimidazoles / pharmacology*
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Cytochrome P-450 Enzyme Inhibitors
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Cytochrome P-450 Enzyme System / metabolism
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Drug Design
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Humans
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Mice
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Microsomes, Liver / metabolism
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Obesity / drug therapy
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Pyridones / chemical synthesis
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Pyridones / chemistry*
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Pyridones / metabolism
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Pyridones / pharmacology*
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Rats
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Receptors, Neuropeptide Y / antagonists & inhibitors*
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Receptors, Neuropeptide Y / metabolism
Substances
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Benzimidazoles
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Cytochrome P-450 Enzyme Inhibitors
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Pyridones
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Receptors, Neuropeptide Y
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neuropeptide Y5 receptor
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Cytochrome P-450 Enzyme System