Synthesis,SAR study,and biological evaluation of novel 2,3-dihydro-1H-imidazo[1,2-a]benzimidazole derivatives as phosphodiesterase 10A inhibitors |
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| Authors: | Ayaka Chino Shugo Honda Masataka Morita Koichi Yonezawa Wataru Hamaguchi Yasushi Amano Hiroyuki Moriguchi Mayako Yamazaki Masaki Aota Masaki Tomishima Naoyuki Masuda |
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| Institution: | Functional Molecules, Modality Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan |
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| 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. |
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| Keywords: | Corresponding author PDE10A inhibitor Schizophrenia Brain penetration P-gp liability Y-maze |
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