HCV NS3/4a protease inhibitors are proven therapeutic agents against chronic hepatitis C virus infection, with boceprevir and telaprevir having recently received regulatory approval as add-on therapy to pegylated interferon/ribavirin for patients harboring genotype 1 infections. Overcoming antiviral resistance, broad genotype coverage, and a convenient dosing regimen are important attributes for future agents to be used in combinations without interferon. In this communication, we report the preclinical profile of MK-5172, a novel P2-P4 quinoxaline macrocyclic NS3/4a protease inhibitor currently in clinical development. The compound demonstrates subnanomolar activity against a broad enzyme panel encompassing major hepatitis C virus (HCV) genotypes as well as variants resistant to earlier protease inhibitors. In replicon selections, MK-5172 exerted high selective pressure, which yielded few resistant colonies. In both rat and dog, MK-5172 demonstrates good plasma and liver exposures, with 24-h liver levels suggestive of once-daily dosing. When administered to HCV-infected chimpanzees harboring chronic gt1a or gt1b infections, MK-5172 suppressed viral load between 4 to 5 logs at a dose of 1 mg/kg of body weight twice daily (b.i.d.) for 7 days. Based on its preclinical profile, MK-5172 is anticipated to be broadly active against multiple HCV genotypes and clinically important resistance variants and highly suited for incorporation into newer all-oral regimens.C hronic hepatitis C virus (HCV) infection afflicts more than 170 million people worldwide and is the major etiological cause of fibrosis, liver cirrhosis, and hepatocellular carcinoma (20,53). Current treatment relies on a backbone of interferon and ribavirin, a regimen with poor tolerability and toxicity (31, 34). Efforts to develop novel therapies to improve treatment have focused largely on direct acting antiviral agents (DAAs) (19), which therapeutically intervene with virally encoded components essential for HCV replication.Hepatitis C virus, a member of the Flaviviridae family of viruses in the Hepacivirus genus, is encoded by a 9.6-kb positivestrand RNA genome (8). It is initially translated into a single polypeptide that is subsequently cleaved into individual protein components by a combination of both host-and virally encoded proteases (2, 38). HCV protease inhibitors currently in clinical development span a variety of structural classes. The most advanced of these are keto amide compounds, which covalently bind to the active-site serine of the protease in a slowly reversible manner. Boceprevir (29) and telaprevir (37), both from this class, recently received regulatory approval as add-on therapy to pegylated interferon/ribavirin in the treatment of genotype 1-infected patients. A number of rapidly reversible NS3/4a protease inhibitors, including the P1-P3 constrained macrocyclic inhibitors TMC 435 (23) and danoprevir (45), the P2-P4 constrained macrocyclic inhibitor vaniprevir (33), the linear inhibitors BI 201335 (52), BMS650032 (47), and ABT-450 ...