Lead optimization of spiropyrazolopyridones: A new and potent class of dengue virus inhibitors

Bin Zou, Wai Ling Chan, Mei Ding, Seh Yong Leong, Shahul Nilar, Peck Gee Seah, Wei Liu, Ratna Karuna, Francesca Blasco, Andy Yip, Alex Chao, Agatha Susila, Hongping Dong, Qing Yin Wang, Hao Ying Xu, Katherine Chan, Kah Fei Wan, Feng Gu, Thierry T. Diagana, Trixie WagnerIna Dix, Pei Yong Shi, Paul W. Smith

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)344-348
Number of pages5
JournalACS Medicinal Chemistry Letters
Volume6
Issue number3
DOIs
StatePublished - Mar 12 2015
Externally publishedYes

Keywords

  • Dengue virus (DENV)
  • lead optimization
  • spiropyrazolopyridones
  • structure-activity relationship

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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    Zou, B., Chan, W. L., Ding, M., Leong, S. Y., Nilar, S., Seah, P. G., Liu, W., Karuna, R., Blasco, F., Yip, A., Chao, A., Susila, A., Dong, H., Wang, Q. Y., Xu, H. Y., Chan, K., Wan, K. F., Gu, F., Diagana, T. T., ... Smith, P. W. (2015). Lead optimization of spiropyrazolopyridones: A new and potent class of dengue virus inhibitors. ACS Medicinal Chemistry Letters, 6(3), 344-348. https://doi.org/10.1021/ml500521r