Design and synthesis of novel benzimidazole derivatives as phosphodiesterase 10A inhibitors with reduced CYP1A2 inhibition

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 benzimi...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2013-12, Vol.21 (24), p.7612-7623
Main Authors: Hamaguchi, Wataru, Masuda, Naoyuki, Isomura, Mai, Miyamoto, Satoshi, Kikuchi, Shigetoshi, Amano, Yasushi, Honbou, Kazuya, Mihara, Takuma, Watanabe, Toshihiro
Format: Article
Language:English
Subjects:
Benzimidazole
Benzimidazoles - chemical synthesis
Benzimidazoles - chemistry
Benzimidazoles - pharmacology
chemistry
Crystallography, X-Ray
CYP1A2
Cytochrome P-450 CYP1A2 - metabolism
Cytochrome P-450 CYP1A2 Inhibitors
Dose-Response Relationship, Drug
Drug Design
Humans
Models, Molecular
Molecular Structure
PDE10A inhibitor
Phosphodiesterase Inhibitors - chemical synthesis
Phosphodiesterase Inhibitors - chemistry
Phosphodiesterase Inhibitors - pharmacology
Phosphoric Diester Hydrolases - metabolism
quinoline
Recombinant Proteins - metabolism
Schizophrenia
Structure-Activity Relationship
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Summary: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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2013.10.035