Highlights of the Structure-Activity Relationships of Benzimidazole Linked Pyrrolidines Leading to the Discovery of the Hepatitis C Virus NS5A Inhibitor Pibrentasvir (ABT-530)
| Autor: | Ryan G. Keddy, Warren M. Kati, Tami Pilot-Matias, Nelson Lissa T, DeAnne Stolarik, Tatyana Dekhtyar, Rubina Mondal, Thomas Reisch, A. Chris Krueger, Hutchinson Douglas K, Donner Pamela L, John T. Randolph, Wenqing Gao, David A. Betebenner, Clarence J. Maring, Preethi Krishnan, Neeta S. Panchal, Christine A. Collins, Todd W. Rockway, Yi Gao, Teresa I. Ng, David W A Beno, John K. Pratt, Dachun Liu, Sachin V. Patel, Charles A. Flentge, Mark A. Matulenko, Rolf Wagner |
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| Rok vydání: | 2018 |
| Předmět: |
Pyrrolidines
Genotype viruses Hepatitis C virus Hepacivirus medicine.disease_cause Virus Replication Antiviral Agents Virus 03 medical and health sciences chemistry.chemical_compound Mice Structure-Activity Relationship 0302 clinical medicine Interferon Drug Discovery medicine Animals Tissue Distribution NS5A biology Chemistry Ribavirin virus diseases biochemical phenomena metabolism and nutrition biology.organism_classification Virology digestive system diseases Ombitasvir Pibrentasvir 030220 oncology & carcinogenesis Drug Design Molecular Medicine 030211 gastroenterology & hepatology Benzimidazoles medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 61(9) |
| ISSN: | 1520-4804 |
| Popis: | Curative interferon and ribavirin sparing treatments for hepatitis C virus (HCV)-infected patients require a combination of mechanistically orthogonal direct acting antivirals. A shared component of these treatments is usually an HCV NS5A inhibitor. First generation FDA approved treatments, including the component NS5A inhibitors, do not exhibit equivalent efficacy against HCV virus genotypes 1-6. In particular, these first generation NS5A inhibitors tend to select for viral drug resistance. Ombitasvir is a first generation HCV NS5A inhibitor included as a key component of Viekira Pak for the treatment of patients with HCV genotype 1 infection. Since the launch of next generation HCV treatments, functional cure for genotype 1-6 HCV infections has been achieved, as well as shortened treatment duration across a wider spectrum of genotypes. In this paper, we show how we have modified the anchor, linker, and end-cap architecture of our NS5A inhibitor design template to discover a next generation NS5A inhibitor pibrentasvir (ABT-530), which exhibits potent inhibition of the replication of wild-type genotype 1-6 HCV replicons, as well as improved activity against replicon variants demonstrating resistance against first generation NS5A inhibitors. |
| Databáze: | OpenAIRE |
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