Discovery and Optimization of a-Mangostin Derivatives as Novel PDE4 Inhibitors for the Treatment of Vascular Dementia

被引：41

作者：

Liang, Jinhao ^{[1
]}

Huang, Yi-You ^{[2
]}

Zhou, Qian ^{[2
]}

Gao, Yuqi ^{[2
]}

Li, Zhe ^{[2
]}

Wu, Deyan ^{[2
]}

Yu, Si ^{[1
]}

Guo, Lei ^{[2
]}

Chen, Zhen ^{[3
,4
]}

Huang, Ling ^{[2
]}

Liang, Steven H. ^{[3
,4
]}

He, Xixin ^{[1
]}

Wu, Ruibo ^{[2
]}

Luo, Hai-Bin ^{[2
]}

机构：

[1] Guangzhou Univ Chinese Med, Sch Pharmaceut Sci, Guangzhou 510006, Peoples R China

[2] Sun Yat Sen Univ, Sch Pharmaceut Sci, Guangzhou 510006, Peoples R China

[3] Massachusetts Gen Hosp, Dept Radiol, Div Nucl Med & Mol Imaging, Boston, MA 02114 USA

[4] Harvard Med Sch, Boston, MA 02114 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2020年 / 63卷 / 06期

关键词：

MEMORY DEFICITS; PHOSPHODIESTERASE; RECOGNITION; EXPRESSION; ROLIPRAM; COMPLEX; DESIGN; DRUGS;

D O I：

10.1021/acs.jmedchem.0c00060

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

To validate PDE4 inhibitors as novel therapeutic agents against vascular dementia (VaD), 25 derivatives were discovered from the natural inhibitor alpha-mangostin (IC50 = 1.31 mu M). Hit-to-lead optimization identified a novel and selective PDE4 inhibitor 4e (IC50 = 17 nM), which adopted a different binding pattern from PDE4 inhibitors roflumilast and rolipram. Oral administration of 4e at a dose of 10 mg/kg exhibited remarkable therapeutic effects in a VaD model and did not cause emesis to beagle dogs, indicating its potential as a novel anti-VaD agent.

引用

页码：3370 / 3380

页数：11

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