Your browser doesn't support javascript.
Potency and pharmacokinetics of GS-441524 derivatives against SARS-CoV-2.
Wei, Daibao; Hu, Tianwen; Zhang, Yumin; Zheng, Wei; Xue, Haitao; Shen, Jingshan; Xie, Yuanchao; Aisa, Haji A.
  • Wei D; State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, South Beijing Road 40-1, Urumqi 830011, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049,
  • Hu T; State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, South Beijing Road 40-1, Urumqi 830011, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049,
  • Zhang Y; State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei 430071, China.
  • Zheng W; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
  • Xue H; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
  • Shen J; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
  • Xie Y; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. Electronic address: yuanchaoxie@simm.ac.cn.
  • Aisa HA; State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, South Beijing Road 40-1, Urumqi 830011, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049,
Bioorg Med Chem ; 46: 116364, 2021 09 15.
Article in English | MEDLINE | ID: covidwho-1406212
ABSTRACT
The nucleoside metabolite of remdesivir, GS-441524 displays potent anti-SARS-CoV-2 efficacy, and is being evaluated in clinical as an oral antiviral therapeutic for COVID-19. However, this nucleoside has a poor oral bioavailability in non-human primates, which may affect its therapeutic efficacy. Herein, we reported a variety of GS-441524 analogs with modifications on the base or the sugar moiety, as well as some prodrug forms, including five isobutyryl esters, two l-valine esters, and one carbamate. Among the new nucleosides, only the 7-fluoro analog 3c had moderate anti-SARS-CoV-2 activity, and its phosphoramidate prodrug 7 exhibited reduced activity in Vero E6 cells. As for the prodrugs, the 3'-isobutyryl ester 5a, the 5'-isobutyryl ester 5c, and the tri-isobutyryl ester 5g hydrobromide showed excellent oral bioavailabilities (F = 71.6%, 86.6% and 98.7%, respectively) in mice, which provided good insight into the pharmacokinetic optimization of GS-441524.
Subject(s)
Keywords
Fulltext
Print
XML
PubMed Links
Search on Google

Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Adenosine / SARS-CoV-2 Type of study: Experimental Studies / Prognostic study Limits: Animals Language: English Journal: Bioorg Med Chem Journal subject: Biochemistry / Chemistry Year: 2021 Document Type: Article

Similar

MEDLINE
LILACS
LIS
Fulltext
Print
XML
PubMed Links
Search on Google

Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Adenosine / SARS-CoV-2 Type of study: Experimental Studies / Prognostic study Limits: Animals Language: English Journal: Bioorg Med Chem Journal subject: Biochemistry / Chemistry Year: 2021 Document Type: Article