2. Academic Validation
  3. Synthesis and evaluation of 2'-dihalo ribonucleotide prodrugs with activity against hepatitis C virus

Synthesis and evaluation of 2'-dihalo ribonucleotide prodrugs with activity against hepatitis C virus

  • Bioorg Med Chem. 2020 Jan 1;28(1):115208. doi: 10.1016/j.bmc.2019.115208.
A Chris Krueger 1,  Hui-Ju Chen 2,  John T Randolph 3,  Brian S Brown 3,  Geoff T Halvorsen 3,  Howard R Heyman 3,  Tongmei Li 3,  Christopher C Marvin 3,  Jason P Shanley 3,  Eric A Voight 3,  Daniel A J Bow 3,  Cecilia Van Handel 3,  Vincent Peterkin 3,  Robert A Carr 3,  DeAnne Stolarik 3,  Tatyana Dekhtyar 3,  Michelle L Irvin 3,  Preethi Krishnan 3,  Rodger F Henry 3,  Rolf Wagner 3,  David A DeGoey 3
Affiliations

Affiliations

  • 1 AbbVie Incorporated, Global Pharmaceutical Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, United States. Electronic address: a.chris.krueger@abbvie.com.
  • 2 AbbVie Incorporated, Global Pharmaceutical Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, United States. Electronic address: hui-ju.chen@abbvie.com.
  • 3 AbbVie Incorporated, Global Pharmaceutical Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, United States.
PMID: 31740203 DOI: 10.1016/j.bmc.2019.115208
Abstract

Hepatitis C virus (HCV) nucleoside inhibitors have been a key focus of nearly 2 decades of HCV drug research due to a high barrier to drug resistance and pan-genotypic activity profile provided by molecules in this drug class. Our investigations focused on several potent 2'-halogenated uridine-based HCV polymerase inhibitors, resulting in the discovery of novel 2'-deoxy-2'-dihalo-uridine analogs that are potent inhibitors in replicon assays for all genotypes. Further studies to improve in vivo performance of these nucleoside inhibitors identified aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrugs 18a and 18c, which provide high levels of the active triphosphate in dog liver. AIBEE prodrug 18c was compared with sofosbuvir (1) by co-dosing both compounds by oral administration in dog (5 mg/kg each) and measuring liver concentrations of the active triphosphate metabolite at both 4 and 24 h post dosing. In this study, 18c provided liver triphosphate concentrations that were 6-fold higher than sofosbuvir (1) at both biopsy time points, suggesting that 18c could be a highly effective agent for treating HCV infected patients in the clinic.

Keywords

Antiviral; HCV; Hepatitis C; NS5B.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z