John T. Randolph, *Charles A. Flentge, Sachin V. Patel, Lissa Nelson, *Rubina Mondal, Neeta Mistry, Tom Reisch, Tatyana Dekhtyar, Preethi Krishnan, Tami Pilot-Matias, *David W. A. Beno, Rolf Wagner, Warren M. Kati AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL 60064; *formerly employed by Abbott Laboratories HCV NS5A inhibitors are key components of recently approved drug combinations that are highly effective for treating HCV infections. Clinical studies have identified viruses containing variants within the NS5A protein that render the virus highly resistant to treatment with first generation NS5A inhibitors. Thus, identifying compounds that are potent inhibitors of HCV replicons possessing these clinically important resistance-associated mutations figured prominently in our research effort to identify a second-generation NS5A inhibitor for development. We discovered a series of symmetrical NS5A inhibitors containing fluorobenzimidazole groups linking the central pyrrolidine core with the dipeptide-derived endcaps. These compounds maintain broad genotype HCV activity and limited resistance to genotype 1 replicons containing clinically-relevant NS5A variants at positions 28, 30, and 93. SAR studies that identified these inhibitors, including PK properties for leading compounds, will be presented. Disclosures: JTR, SVP, LN, NM, TR, TD, PK, TPM, RW and WMK are employees of AbbVie. CAF, RM and DWAB were employees of Abbott at the time of the study. The design, study conduct, and financial support for the study were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.

Discovery of fluorobenzimidazole HCV NS5A inhibitors

251st National Meeting (2016)

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