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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. 2019
Ayaka Chino, and
Shugo Honda, and
Masataka Morita, and
Koichi Yonezawa, and
Wataru Hamaguchi, and
Yasushi Amano, and
Hiroyuki Moriguchi, and
Mayako Yamazaki, and
Masaki Aota, and
Masaki Tomishima, and
Naoyuki Masuda
Functional Molecules, Modality Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. Electronic address: ayaka.chino@astellas.com.
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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