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Journal article
Design, Synthesis, and Biological Evaluation of Triazolo-pyrimidine Derivatives as Novel Inhibitors of Hepatitis B Virus Surface Antigen (HBsAg) Secretion
Journal of medicinal chemistry, v 54(16), pp 5660-5670
25 Aug 2011
PMID: 21786803
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The high levels of hepatitis B virus (HBV) surface antigen (HBsAg)-bearing subviral particles in the serum of chronically infected individuals play an important role in suppressing HBV-specific immune response and are only mildly affected by the current small molecule therapies. Thus, a therapy that specifically reduces HBsAg serum levels could be used in combination therapy with nucleos(t)ide drugs or permit therapeutic vaccination for the treatment of HBV infection. Herein, we report the design, synthesis, and evaluation of novel triazolo-pyrimidine inhibitors (1, 3, and 4) of HBsAg cellular secretion, with activity against drug-resistant HBV variants. Extensive SAR led to substantial improvements in the EC50 of the parent compound, 5 (HBF-0259), with the best being 3c, with EC50 = 1.4 +/- 0.4 mu M, SI >= 36. The lead candidates, both la (PBHBV-001) and 3c (PBHBV-2-15), were well-tolerated in both normal and HBV-transgenic mice and exhibited acceptable pharmacokinetics and bioavailability in Sprague-Dawley rats.
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Details
- Title
- Design, Synthesis, and Biological Evaluation of Triazolo-pyrimidine Derivatives as Novel Inhibitors of Hepatitis B Virus Surface Antigen (HBsAg) Secretion
- Creators
- Wenquan Yu - Tianjin University of Science and TechnologyGaily Goddard - Hepatitis B Fdn, Inst Hepatitis & Virus Res, Doylestown, PA 18902 USAElizabeth Clearfield - Hepatitis B FoundationCourtney Mills - Hepatitis B FoundationTong Xiao - PharmabridgeHaitao Guo - Drexel UniversityJohn D. Morrey - Utah State UniversityNeil E. Motter - Utah State UniversityKang Zhao - Tianjin UniversityTimothy M. Bock - Hepatitis B Fdn, Inst Hepatitis & Virus Res, Doylestown, PA 18902 USAAndrea Cuconati - Hepatitis B FoundationXiaodong Xu - Hepatitis B Foundation
- Publication Details
- Journal of medicinal chemistry, v 54(16), pp 5660-5670
- Publisher
- American Chemical Society; Washington, DC
- Number of pages
- 11
- Grant note
- Commonwealth of Pennsylvania 1R43AI077123-01A1; N01-AI50036 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Hepatitis B Foundation R43AI077123 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000294077300003
- Scopus ID
- 2-s2.0-80051865054
- Other Identifier
- 991019168777604721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Chemistry, Medicinal