Abstract
A novel class of phosphodiesterase 10A (PDE10A) inhibitors with reduced CYP1A2 inhibition were designed and synthesized starting from 2-{[(1-phenyl-1H-benzimidazol-6-yl)oxy]methyl}quinoline (1). Introduction of an isopropyl group at the 2-position and a methoxy group at the 5-position of the benzimidazole ring of lead compound 1 resulted in the identification of 2-{[(2-isopropyl-5-methoxy-1-phenyl-1H-benzimidazol-6-yl)oxy]methyl}quinoline (25b), which exhibited potent PDE10A inhibitory activity with reduced CYP1A2 inhibitory activity compared to compound 1.
Keywords:
Benzimidazole; CYP1A2; PDE10A inhibitor; Schizophrenia.
Copyright © 2013 Elsevier Ltd. All rights reserved.
MeSH terms
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Benzimidazoles / chemical synthesis
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Benzimidazoles / chemistry
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Benzimidazoles / pharmacology*
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Crystallography, X-Ray
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Cytochrome P-450 CYP1A2 / metabolism
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Cytochrome P-450 CYP1A2 Inhibitors*
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Dose-Response Relationship, Drug
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Drug Design*
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Humans
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Models, Molecular
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Molecular Structure
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Phosphodiesterase Inhibitors / chemical synthesis
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Phosphodiesterase Inhibitors / chemistry
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Phosphodiesterase Inhibitors / pharmacology*
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Phosphoric Diester Hydrolases / metabolism*
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Recombinant Proteins / metabolism
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Structure-Activity Relationship
Substances
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Benzimidazoles
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Cytochrome P-450 CYP1A2 Inhibitors
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Phosphodiesterase Inhibitors
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Recombinant Proteins
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benzimidazole
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CYP1A2 protein, human
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Cytochrome P-450 CYP1A2
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PDE10A protein, human
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Phosphoric Diester Hydrolases