ArticleJournal of medicinal chemistry2019
Design of N-Benzoxaborole Benzofuran GSK8175-Optimization of Human Pharmacokinetics Inspired by Metabolites of a Failed Clinical HCV Inhibitor.
Article in Journal of medicinal chemistry, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- Benzoxaboroles Are Inhibitors of the η-Class Carbonic Anhydrase From Plasmodium falciparum.Archiv der Pharmazie · 2026Article
- Recent Advancements in the Diversification and Applications of Boron-Containing Compounds in Medicinal Chemistry.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Electrochemical cyclization of alkynes to construct five-membered nitrogen-heterocyclic rings.Beilstein journal of organic chemistry · 2025Review
- Trends on Potential Boron-containing Drugs by Advancements in Ligand-protein Crystals Complexes.Current medicinal chemistry · 2025Review
- Synthesis of Diarylamines via Nitrosonium-Initiated C-N Bond Formation.The Journal of organic chemistry · 2024Article
- Identification of Boronate-Containing Diarylpyrimidine Derivatives as Novel HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors.Molecules (Basel, Switzerland) · 2022Article
- Revisiting Viral RNA-Dependent RNA Polymerases: Insights from Recent Structural Studies.Viruses · 2022Review
- Transcriptional differentiation of Trypanosoma brucei during in vitro acquisition of resistance to acoziborole.PLoS neglected tropical diseases · 2021Article
- Recent developments in the medicinal chemistry of single boron atom-containing compounds.Acta pharmaceutica Sinica. B · 2021Review
- Discovery and Development of Antiviral Therapies for Chronic Hepatitis C Virus Infection.Advances in experimental medicine and biology · 2021Article
- Anno 2021: Which antivirals for the coming decade?Annual reports in medicinal chemistry · 2021Article
- Review
- Boronic Acids and Their Derivatives in Medicinal Chemistry: Synthesis and Biological Applications.Molecules (Basel, Switzerland) · 2020Review
- Natural Product Evodiamine with Borate Trigger Unit: Discovery of Potent Antitumor Agents against Colon Cancer.ACS medicinal chemistry letters · 2020Article
Corrections and comments
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Authors and funding
18 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
We previously described the discovery of GSK5852 (1), a non-nucleoside polymerase (NS5B) inhibitor of hepatitis C virus (HCV), in which an N-benzyl boronic acid was essential for potent antiviral activity. Unfortunately, facile benzylic oxidation resulted in a short plasma half-life (5 h) in human volunteers, and a backup program was initiated to remove metabolic liabilities associated with 1. Herein, we describe second-generation NS5B inhibitors including GSK8175 (49), a sulfonamide- N-benzoxaborole analog with low in vivo clearance across preclinical species and broad-spectrum activity against HCV replicons. An X-ray structure of NS5B protein cocrystallized with 49 revealed unique protein-inhibitor interactions mediated by an extensive network of ordered water molecules and the first evidence of boronate complex formation within the binding pocket. In clinical studies, 49 displayed a 60-63 h half-life and a robust decrease in viral RNA levels in HCV-infected patients, thereby validating our hypothesis that reducing benzylic oxidation would improve human pharmacokinetics and lower efficacious doses relative to 1.
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