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

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.

SUBMITTER: Zou B

PROVIDER: S-EPMC4360157 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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

Zou Bin B Chan Wai Ling WL Ding Mei M Leong Seh Yong SY Nilar Shahul S Seah Peck Gee PG Liu Wei W Karuna Ratna R Blasco Francesca F Yip Andy A Chao Alex A Susila Agatha A Dong Hongping H Wang Qing Yin QY Xu Hao Ying HY Chan Katherine K Wan Kah Fei KF Gu Feng F Diagana Thierry T TT Wagner Trixie T Dix Ina I Shi Pei-Yong PY Smith Paul W PW

ACS medicinal chemistry letters 20150202 3

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 ph ...[more]

PMID: 25878766

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