Lead Optimization of Spiropyrazolopyridones: A New and Potent Class of Dengue Virus Inhibitors

被引：63

作者：

Zou, Bin ^{[1
]}

Chan, Wai Ling ^{[1
]}

Ding, Mei ^{[1
]}

Leong, Seh Yong ^{[1
]}

Nilar, Shahul ^{[1
]}

Seah, Peck Gee ^{[1
]}

Liu, Wei ^{[1
]}

Karuna, Ratna ^{[1
]}

Blasco, Francesca ^{[1
]}

Yip, Andy ^{[1
]}

Chao, Alex ^{[1
]}

Susila, Agatha ^{[1
]}

Dong, Hongping ^{[1
]}

Wang, Qing Yin ^{[1
]}

Xu, Hao Ying ^{[1
]}

Chan, Katherine ^{[1
]}

Wan, Kah Fei ^{[1
]}

Gu, Feng ^{[1
]}

Diagana, Thierry T. ^{[1
]}

Wagner, Trixie ^{[2
]}

Dix, Ina ^{[2
]}

Shi, Pei-Yong ^{[1
]}

Smith, Paul W. ^{[1
]}

机构：

[1] Novartis Inst Trop Dis, Singapore 138670, Singapore

[2] Novartis Inst Biomed Res, CH-4056 Basel, Switzerland

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2015年 / 6卷 / 03期

关键词：

Dengue virus (DENV); spiropyrazolopyridones; structure-activity relationship; lead optimization; VIRAL NS4B PROTEIN; REPLICATION; TARGETS; DERIVATIVES; DRUGS;

D O I：

10.1021/ml500521r

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Spiropyrazolopyridone 1 was identified, as a novel dengue virus (DENY) inhibitor, from a DENV serotype 2 (DENV-2) high throughput phenotypic screen. As a general trend within this chemical class, chiral resolution of the racemate revealed that R enantiomer was significantly more potent than the S. Cell based lead optimization of the spiropyrazolopyridones focusing on improving the physico-chemical properties is described. As a result, an optimal compound 14a, with balanced in vitro potency and pharmacokinetic profile, achieved about 1.9 log viremia reduction at 3 X 50 mg/kg (bid) or 3 X 100 mg/kg (QD) oral doses in the dengue in vivo mouse efficacy model.

引用

页码：344 / 348

页数：5

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