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Highlights of the Structure–Activity Relationships of Benzimidazole Linked Pyrrolidines Leading to the Discovery of the Hepatitis C Virus NS5A Inhibitor Pibrentasvir (ABT-530)

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posted on 13.04.2018, 00:00 by Rolf Wagner, John T. Randolph, Sachin V. Patel, Lissa Nelson, Mark A. Matulenko, Ryan Keddy, John K. Pratt, Dachun Liu, A. Chris Krueger, Pamela L. Donner, Douglas K. Hutchinson, Charles Flentge, David Betebenner, Todd Rockway, Clarence J. Maring, Teresa I. Ng, Preethi Krishnan, Tami Pilot-Matias, Christine Collins, Neeta Panchal, Thomas Reisch, Tatyana Dekhtyar, Rubina Mondal, DeAnne F. Stolarik, Yi Gao, Wenqing Gao, David A. Beno, Warren M. Kati
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.