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

Spiropyrazolopyridone 1 was identified, as a novel dengue virus (DENV) 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. C...

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Published in:ACS medicinal chemistry letters 2015-03, Vol.6 (3), p.344-348
Main Authors: Zou, Bin, Chan, Wai Ling, Ding, Mei, Leong, Seh Yong, Nilar, Shahul, Seah, Peck Gee, Liu, Wei, Karuna, Ratna, Blasco, Francesca, Yip, Andy, Chao, Alex, Susila, Agatha, Dong, Hongping, Wang, Qing Yin, Xu, Hao Ying, Chan, Katherine, Wan, Kah Fei, Gu, Feng, Diagana, Thierry T, Wagner, Trixie, Dix, Ina, Shi, Pei-Yong, Smith, Paul W
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Language:English
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Letter
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Summary:Spiropyrazolopyridone 1 was identified, as a novel dengue virus (DENV) 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 physicochemical 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 × 50 mg/kg (bid) or 3 × 100 mg/kg (QD) oral doses in the dengue in vivo mouse efficacy model.
ISSN:1948-5875
1948-5875
DOI:10.1021/ml500521r