title: 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.
authors: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, Singapore 138670, Singapore.
authors: Bin
authors: B
authors: Zou
authors: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, Singapore 138670, Singapore.
authors: Wai Ling
authors: WL
authors: Chan
authors: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, Singapore 138670, Singapore.
authors: Mei
authors: M
authors: Ding
authors: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, Singapore 138670, Singapore.
authors: Seh Yong
authors: SY
authors: Leong
authors: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, Singapore 138670, Singapore.
authors: Shahul
authors: S
authors: Nilar
authors: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, Singapore 138670, Singapore.
authors: Peck Gee
authors: PG
authors: Seah
authors: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, Singapore 138670, Singapore.
authors: Wei
authors: W
authors: Liu
authors: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, Singapore 138670, Singapore.
authors: Ratna
authors: R
authors: Karuna
authors: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, Singapore 138670, Singapore.
authors: Francesca
authors: F
authors: Blasco
authors: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, Singapore 138670, Singapore.
authors: Andy
authors: A
authors: Yip
authors: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, Singapore 138670, Singapore.
authors: Alex
authors: A
authors: Chao
authors: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, Singapore 138670, Singapore.
authors: Agatha
authors: A
authors: Susila
authors: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, Singapore 138670, Singapore.
authors: Hongping
authors: H
authors: Dong
authors: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, Singapore 138670, Singapore.
authors: Qing Yin
authors: QY
authors: Wang
authors: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, Singapore 138670, Singapore.
authors: Hao Ying
authors: HY
authors: Xu
authors: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, Singapore 138670, Singapore.
authors: Katherine
authors: K
authors: Chan
authors: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, Singapore 138670, Singapore.
authors: Kah Fei
authors: KF
authors: Wan
authors: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, Singapore 138670, Singapore.
authors: Feng
authors: F
authors: Gu
authors: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, Singapore 138670, Singapore.
authors: Thierry T
authors: TT
authors: Diagana
authors: Novartis Institute for Biomedical Research , Basel CH-4056, Switzerland.
authors: Trixie
authors: T
authors: Wagner
authors: Novartis Institute for Biomedical Research , Basel CH-4056, Switzerland.
authors: Ina
authors: I
authors: Dix
authors: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, Singapore 138670, Singapore.
authors: Pei-Yong
authors: PY
authors: Shi
authors: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, Singapore 138670, Singapore.
authors: Paul W
authors: PW
authors: Smith
keywords: Dengue virus (DENV); lead optimization; spiropyrazolopyridones; structure−activity relationship