Synthesis, SAR study, and biological evaluation of novel 2,3-dihydro-1H-imidazo[1,2-α] benzimidazole derivatives as phosphodiesterase 10A inhibitors

被引：5

作者：

Chino, Ayaka ^{[1
]}

Honda, Shugo ^{[1
]}

Morita, Masataka ^{[1
]}

Yonezawa, Koichi ^{[1
]}

Hamaguchi, Wataru ^{[1
]}

Amano, Yasushi ^{[1
]}

Moriguchi, Hiroyuki ^{[1
]}

Yamazaki, Mayako ^{[1
]}

Aota, Masaki ^{[1
]}

Tomishima, Masaki ^{[1
]}

Masuda, Naoyuki ^{[1
]}

机构：

[1] Astellas Pharma Inc, Drug Discovery Res, Modal Res Labs, Funct Mol, 21 Miyukigaoka, Tsukuba, Ibaraki 3058585, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2019年 / 27卷 / 16期

关键词：

PDE10A inhibitor; Schizophrenia; Brain penetration; P-gp liability; Y-maze; PDE10A INHIBITORS; DISCOVERY; SCHIZOPHRENIA; RECOGNITION; ANTAGONIST; STRIATUM; SYMPTOMS; DESIGN; POTENT; MODEL;

D O I：

10.1016/j.bmc.2019.07.010

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Phosphodiesterase 10A (PDE10A) inhibitors were designed and synthesized based on the dihydro-imidazo-benzimidazole 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.

引用

收藏

页码：3692 / 3706

页数：15

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