Abstract
A series of 3-[6-(4-substituted-piperazin-1-yl)-4-methyl-1H-benzimidazol-2-yl]-1H-pyridine-2-one were synthesized to modulate CYP3A4 inhibition and improve aqueous solubility of our prototypical compound BMS-536924 (1), while maintaining potent IGF-1R inhibitory activity. Structure-activity and structure-solubility studies led to the identification of BMS-577098 (27), which demonstrates oral in vivo efficacy in animal models. The improvement was achieved by replacing morpholine with more polar bio-isoster piperazine and modulating the basicity of distal nitrogen with appropriate substitutions.
Copyright 2010 Elsevier Ltd. All rights reserved.
MeSH terms
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Administration, Oral
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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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Benzimidazoles / pharmacology
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Cytochrome P-450 CYP3A / metabolism
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Cytochrome P-450 CYP3A Inhibitors
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Humans
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Mice
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Mice, Nude
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Piperazines / chemical synthesis
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Piperazines / chemistry*
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Piperazines / pharmacokinetics
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacology
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Pyridones / chemical synthesis
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Pyridones / chemistry*
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Pyridones / pharmacokinetics
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Pyridones / pharmacology
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Rats
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Receptor, IGF Type 1 / antagonists & inhibitors
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Receptor, IGF Type 1 / metabolism
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Structure-Activity Relationship
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Xenograft Model Antitumor Assays
Substances
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BMS 536924
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BMS 577098
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Benzimidazoles
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Cytochrome P-450 CYP3A Inhibitors
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Piperazines
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Protein Kinase Inhibitors
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Pyridones
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benzimidazole
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Cytochrome P-450 CYP3A
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CYP3A4 protein, human
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Receptor, IGF Type 1