DOI: 10.1002/cmdc.201300343 Discovery of MK-8742: An HCV NS5A Inhibitor with Broad Genotype Activity Craig A. Coburn,* [a] Peter T. Meinke, [a] Wei Chang, [e] Christine M. Fandozzi, [c] Donald J. Graham, [b] Bin Hu, [e] Qian Huang, [b] Stacia Kargman, [d] Joseph Kozlowski, [a] Rong Liu, [b] John A. McCauley, [a] Amin A. Nomeir, [c] Richard M. Soll, [e] Joseph P. Vacca, [a] Dahai Wang, [e] Hao Wu, [e] Bin Zhong, [e] David B. Olsen, [b] and Steven W. Ludmerer* [b] Introduction The World Health Organization (WHO) estimates that ~ 3% of the world’s population are chronically infected with hepatitis C virus (HCV). Although HCV infection has both acute and chron- ic forms, most of the morbidity associated with infection is re- alized through the development of chronic liver disease in a subset of infected people years after initial acquisition of the infection. [1] HCV displays a high degree of genetic heterogenei- ty and can be classified into six major genotypes (GT1–6) and a series of subtypes (a,b,c,…), with genotypes 1a and 1b ac- counting for ~ 60 % of all infections. Current interferon-based therapy for chronic hepatitis C is limited by both efficacy and tolerability. Furthermore, the abili- ty to achieve a sustained virologic response is largely depen- dent on the HCV genotype and duration of treatment. An im- portant goal of future HCV therapy is to develop direct-acting antivirals in order to: 1) provide an all-oral interferon-free regi- men, 2) decrease overall treatment durations, 3) provide broad- er coverage of HCV patient populations (e.g., GT2/GT3/GT4 in- fections, interferon-intolerant patients, and other difficult-to- treat populations), and 4) improve the overall safety and toler- ability of HCV treatment regimens. [2] Given the propensity of HCV for generating genetic diversity, an interferon-free regi- men will likely require two or more potent direct-acting com- pounds with non-overlapping resistance profiles in order to suppress the broadest-spectrum infections. The HCV NS5A protein is a multifunctional RNA binding pro- tein essential for viral replication. NS5A has no known enzy- matic function, but has been shown to serve multiple func- tions at various stages of the life cycle, including viral replica- tion and virion assembly. [3] A landmark proof-of-concept study validated NS5A as a ther- apeutic target when it was demonstrated that a single dose of the NS5A inhibitor daclatasvir could effect a rapid virologic re- sponse in GT1-infected patients. [4] This result precipitated activ- ity in the field and made NS5A a target for many research groups. [5] Improvements in potency across a broad spectrum of HCV genotypes and mutants while maintaining favorable physical and pharmacokinetic parameters may lead to improved NS5A inhibitors with a higher barrier to resistance. Toward this end, a concerted research effort aimed at combining the structural components from both internal and literature compounds led to a series of potent NS5A inhibitors containing a central The NS5A protein plays a critical role in the replication of HCV and has been the focus of numerous research efforts over the past few years. NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays, making them attrac- tive components for inclusion in all oral combination regimens. Early work in the NS5A arena led to the discovery of our first clinical candidate, MK-4882 [2-((S)-pyrrolidin-2-yl)-5-(2-(4-(5-((S)- pyrrolidin-2-yl)-1H-imidazol-2-yl)phenyl)benzofuran-5-yl)-1H- imidazole]. While preclinical proof-of-concept studies in HCV- infected chimpanzees harboring chronic genotype 1 infections resulted in significant decreases in viral load after both single- and multiple-dose treatments, viral breakthrough proved to be a concern, thus necessitating the development of compounds with increased potency against a number of genotypes and NS5A resistance mutations. Modification of the MK-4882 core scaffold by introduction of a cyclic constraint afforded a series of tetracyclic inhibitors, which showed improved virologic pro- files. Herein we describe the research efforts that led to the discovery of MK-8742, a tetracyclic indole-based NS5A inhibi- tor, which is currently in phase 2b clinical trials as part of an all-oral, interferon-free regimen for the treatment of HCV infec- tion. [a] Dr. C. A. Coburn, Dr. P.T. Meinke, Dr. J. Kozlowski, Dr. J. A. McCauley, Dr. J. P. Vacca Department of Medicinal Chemistry, Merck and Company, Inc. West Point, PA 19486 (USA) E-mail : craig_coburn@merck.com [b] D. J. Graham, Q. Huang, Dr. R. Liu, Dr. D. B. Olsen, Dr. S. W. Ludmerer Department of Antiviral Research, Merck and Company, Inc. West Point, PA 19486 (USA) E-mail : steven_ludmerer@merck.com [c] Dr. C. M. Fandozzi, Dr. A. A. Nomeir Department of Preclinical Pharmacokinetics and Drug Metabolism (Merck) [d] Dr. S. Kargman Department of In Vitro Pharmacology (Merck) [e] W. Chang, Dr. B. Hu, Dr. R. M. Soll, Dr. D. Wang, Dr. H. Wu, Dr. B. Zhong Department of Medicinal Chemistry, WuXi AppTec Shanghai, 200131 China  2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim ChemMedChem 2013, 8, 1930 – 1940 1930 CHEMMEDCHEM FULL PAPERS