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Start Over Author "Yongfei Huang" Journal journal of medicinal chemistry
3 results on '"Yongfei Huang"'

1. Synthesis and Anti-HCV Activity of Sugar-Modified Guanosine Analogues: Discovery of AL-611 as an HCV NS5B Polymerase Inhibitor for the Treatment of Chronic Hepatitis C

Author

Antitsa Dimitrova Stoycheva, Leonid Beigelman, Tongqian Chen, Kenneth Shaw, Vivek K. Rajwanshi, Zhinan Jin, Andreas Jekle, Yujian Hu, Kusum Gupta, Caroline Williams, Amy Fung, Guangyi Wang, Vladimir Serebryany, Natalia B. Dyatkina, Xiangyang Wu, Marija Prhavc, Jerome Deval, David B. Smith, Wensheng Huang, Yuen Tam, and Yongfei Huang

Subjects
0303 health sciences, Chemistry, Hepatitis C virus, Guanosine, Phosphoramidate, Pharmacology, Prodrug, medicine.disease, medicine.disease_cause, 01 natural sciences, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, 03 medical and health sciences, Liver disease, chemistry.chemical_compound, In vivo, Drug Discovery, medicine, Molecular Medicine, IC50, Nucleoside, 030304 developmental biology
Abstract

Chronic hepatitis C (CHC) is a major liver disease caused by the hepatitis C virus. The current standard of care for CHC can achieve cure rates above 95%; however, the drugs in current use are administered for a period of 8-16 weeks. A combination of safe and effective drugs with a shorter treatment period is highly desirable. We report synthesis and biological evaluation of a series of 2',3'- and 2',4'-substituted guanosine nucleotide analogues. Their triphosphates exhibited potent inhibition of the HCV NS5B polymerase with IC50 as low as 0.13 μM. In the HCV replicon assay, the phosphoramidate prodrugs of these analogues demonstrated excellent activity with EC50 values as low as 5 nM. A lead compound AL-611 showed high levels of the nucleoside 5'-triphosphate in vitro in primary human hepatocytes and in vivo in dog liver following oral administration.

Published
2020
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2. Synthesis and Anti-HCV Activity of Sugar-Modified Guanosine Analogues: Discovery of

Author

Guangyi, Wang, Natalia, Dyatkina, Marija, Prhavc, Caroline, Williams, Vladimir, Serebryany, Yujian, Hu, Yongfei, Huang, Xiangyang, Wu, Tongqian, Chen, Wensheng, Huang, Vivek K, Rajwanshi, Jerome, Deval, Amy, Fung, Zhinan, Jin, Antitsa, Stoycheva, Kenneth, Shaw, Kusum, Gupta, Yuen, Tam, Andreas, Jekle, David B, Smith, and Leonid, Beigelman

Subjects
Male, Dogs, Animals, Humans, Female, Prodrugs, DNA-Directed RNA Polymerases, Hepacivirus, Enzyme Inhibitors, Viral Nonstructural Proteins, Virus Replication, Antiviral Agents, Guanine Nucleotides
Abstract

Chronic hepatitis C (CHC) is a major liver disease caused by the hepatitis C virus. The current standard of care for CHC can achieve cure rates above 95%; however, the drugs in current use are administered for a period of 8-16 weeks. A combination of safe and effective drugs with a shorter treatment period is highly desirable. We report synthesis and biological evaluation of a series of 2',3'- and 2',4'-substituted guanosine nucleotide analogues. Their triphosphates exhibited potent inhibition of the HCV NS5B polymerase with IC

Published
2020

3. Synthesis and Anti-HCV Activities of 4'-Fluoro-2'-Substituted Uridine Triphosphates and Nucleotide Prodrugs: Discovery of 4'-Fluoro-2'- C-methyluridine 5'-Phosphoramidate Prodrug (AL-335) for the Treatment of Hepatitis C Infection

Author

Yongfei Huang, Leonid Beigelman, Antitsa Dimitrova Stoycheva, Andreas Jekle, Zhinan Jin, Yujian Hu, Jerome Deval, Jinqiao Wan, Hua Tan, Vladimir Serebryany, David B. Smith, Guangyi Wang, Marija Prhavc, Qingling Zhang, Natalia B. Dyatkina, Kenneth Shaw, Amy Fung, Hyunsoon Kang, Xiangyang Wu, Yuen Tam, and Caroline Williams

Subjects
Uracil Nucleotides, Hepatitis C virus, Hepacivirus, Viral Nonstructural Proteins, medicine.disease_cause, 01 natural sciences, Antiviral Agents, 03 medical and health sciences, chemistry.chemical_compound, Dogs, Cell Line, Tumor, Drug Discovery, medicine, Animals, Humans, Nucleotide, Prodrugs, Uridine, 030304 developmental biology, Nucleic Acid Synthesis Inhibitors, chemistry.chemical_classification, 0303 health sciences, Alanine, Phosphoramidate, Hepatitis C, Prodrug, medicine.disease, In vitro, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, chemistry, Biochemistry, Nucleoside triphosphate, Molecular Medicine, Phosphoramides, Replicon
Abstract

We report the synthesis and biological evaluation of a series of 4'-fluoro-2'- C-substituted uridines. Triphosphates of the uridine analogues exhibited a potent inhibition of hepatitis C virus (HCV) NS5B polymerase with IC50 values as low as 27 nM. In an HCV subgenomic replicon assay, the phosphoramidate prodrugs of these uridine analogues demonstrated a very potent activity with EC50 values as low as 20 nM. A lead compound AL-335 (53) demonstrated high levels of the nucleoside triphosphate in vitro in primary human hepatocytes and Huh-7 cells as well as in dog liver following a single oral dose. Compound 53 was selected for the clinical development where it showed promising results in phase 1 and 2 trials.

Published
2019

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