| Literature DB >> 25878766 |
Bin Zou1, Wai Ling Chan1, Mei Ding1, Seh Yong Leong1, Shahul Nilar1, Peck Gee Seah1, Wei Liu1, Ratna Karuna1, Francesca Blasco1, Andy Yip1, Alex Chao1, Agatha Susila1, Hongping Dong1, Qing Yin Wang1, Hao Ying Xu1, Katherine Chan1, Kah Fei Wan1, Feng Gu1, Thierry T Diagana1, Trixie Wagner2, Ina Dix2, Pei-Yong Shi1, Paul W Smith1.
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.Entities:
Keywords: Dengue virus (DENV); lead optimization; spiropyrazolopyridones; structure−activity relationship
Year: 2015 PMID： 25878766 PMCID： PMC4360157 DOI： 10.1021/ml500521r
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345