Fragment-Based Discovery of Pyrimido[1,2-b]indazole PDE10A Inhibitors

被引：23

作者：

Chino, Ayaka ^{[1
]}

Seo, Ryushi ^{[1
]}

Amano, Yasushi ^{[1
]}

Namatame, Ichiji ^{[1
]}

Hamaguchi, Wataru ^{[1
]}

Honbou, Kazuya ^{[1
]}

Mihara, Takuma ^{[1
]}

Yamazaki, Mayako ^{[1
]}

Tomishima, Masaki ^{[1
]}

Masuda, Naoyuki ^{[1
]}

机构：

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

来源：

CHEMICAL & PHARMACEUTICAL BULLETIN | 2018年 / 66卷 / 03期

关键词：

phosphodiesterase10A inhibitor; fragment-based drug discovery; schizophrenia; combinatorial synthesis; pyrimido[1,2-b]indazole; PHOSPHODIESTERASE 10A INHIBITORS; PHARMACOLOGICAL EVALUATION; LEAD DISCOVERY; DESIGN; DERIVATIVES; POTENT; IDENTIFICATION; SCHIZOPHRENIA;

D O I：

10.1248/cpb.c17-00836

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

In this study, we report the identification of potent pyrimidoindazoles as phosphodiesterase10A (PDE10A) inhibitors by using the method of fragment-based drug discovery (FBDD). The pyrazolopyridine derivative 2 was found to be a fragment hit compound which could occupy a part of the binding site of PDE10A enzyme by using the method of the X-ray co-crystal structure analysis. On the basis of the crystal structure of compound 2 and PDE10A protein, a number of compounds were synthesized and evaluated, by means of structure activity relationship (SAR) studies, which culminated in the discovery of a novel pyrimidoindazole derivative 13 having good physicochemical properties.

引用

页码：286 / 294

页数：9

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