Discovery of Ledipasvir (GS-5885): A Potent, Once-Daily Oral NS5A Inhibitor for the Treatment of Hepatitis C Virus Infection
| Autor: | Kelly Wang, James G. Taylor, Elsa Mondou, Mike Matles, Yang Zheng-Yu, Yujin Wang, Hongtao Liu, Jianyu Sun, Yang Tian, Guofeng Cheng, Hongyan Guo, Lianhong Xu, Melanie Cornpropst, Jason K. Perry, Michael L. Mitchell, Thorsten Kirschberg, Kato Darryl, Manoj C. Desai, Chris Yang, Neil H. Squires, John O. Link, Terry Kellar, Erik Mogalian, Jay P. Parrish |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Ledipasvir Hepatitis C virus Administration Oral Viral Nonstructural Proteins Pharmacology medicine.disease_cause Antiviral Agents Placebos Rats Sprague-Dawley Structure-Activity Relationship chemistry.chemical_compound Double-Blind Method Pharmacokinetics Drug Discovery medicine Animals Humans Potency Dosing NS5A DNA Primers EC50 Fluorenes Base Sequence Chemistry Hepatitis C Virology Rats Macaca fascicularis Molecular Medicine Benzimidazoles Viral load Half-Life |
| Zdroj: | Journal of Medicinal Chemistry. 57:2033-2046 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm401499g |
| Popis: | A new class of highly potent NS5A inhibitors with an unsymmetric benzimidazole-difluorofluorene-imidazole core and distal [2.2.1]azabicyclic ring system was discovered. Optimization of antiviral potency and pharmacokinetics led to the identification of 39 (ledipasvir, GS-5885). Compound 39 (GT1a replicon EC50 = 31 pM) has an extended plasma half-life of 37–45 h in healthy volunteers and produces a rapid >3 log viral load reduction in monotherapy at oral doses of 3 mg or greater with once-daily dosing in genotype 1a HCV-infected patients. 39 has been shown to be safe and efficacious, with SVR12 rates up to 100% when used in combination with direct-acting antivirals having complementary mechanisms. |
| Databáze: | OpenAIRE |
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