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Synthesis, SAR study, and biological evaluation of novel 2,3-dihydro-1H-imidazo[1,2-a]benzimidazole derivatives as phosphodiesterase 10A inhibitors.
Chino A,
Honda S,
Morita M,
Yonezawa K,
Hamaguchi W,
Amano Y,
Moriguchi H,
Yamazaki M,
Aota M,
Tomishima M,
Masuda N
Bioorg Med Chem 27 3692-3706 (2019)
Abstract
Phosphodiesterase 10A (PDE10A) inhibitors were designed and synthesized based on the dihydro-imidazobenzimidazole scaffold. Compound 5a showed moderate inhibitory activity and good permeability, but unfavorable high P-glycoprotein (P-gp) liability for brain penetration. We performed an optimization study to improve both the P-gp efflux ratio and PDE10A inhibitory activity. As a result, 6d was identified with improved P-gp liability and high PDE10A inhibitory activity. Compound 6d also showed satisfactory brain penetration, suppressed phencyclidine-induced hyperlocomotion and improved MK-801-induced working memory deficit.
We are not aware of any publication which cites or mentions this structure.