John A. McCauley

MK-5172, a Selective Inhibitor of Hepatitis C Virus NS3/4a Protease with Broad Activity across Genotypes and Resistant Variants

ABSTRACT 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.

Discovery of MK-8742: an HCV NS5A inhibitor with broad genotype activity.

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 attractive 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 genotypeu20051 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 profiles. Herein we describe the research efforts that led to the discovery of MK‐8742, a tetracyclic indole‐based NS5A inhibitor, which is currently in phaseu20052b clinical trials as part of an all‐oral, interferon‐free regimen for the treatment of HCV infection.

HEPATITIS C VIRUS NS3 PROTEASE INHIBITORS

Hepatitis C virus (HCV) infection is a major health issue around the world and HCV NS3/4a protease inhibitors have been the focus of intensive research for the past 20 years. From the first identification of substrate-derived peptide inhibitors to the complex, macrocyclic compounds, including paritaprevir and grazoprevir, that are currently available, the field has used structure-based design to confront the issues of potency, resistance and pharmacokinetics. Numerous breakthrough structures from a multitude of companies have led to compounds that are now key components of combination therapies with cure rates of >90%. Herein, we detail the compounds that have advanced to clinical trials including their design and their impact on the NS3/4a protease field.

Preclinical pharmacology and pharmacokinetics of CERC-301, a GluN2B-selective N-methyl-D-aspartate receptor antagonist.

The preclinical pharmacodynamic and pharmacokinetic properties of 4‐methylbenzyl (3S, 4R)‐3‐fluoro‐4‐[(Pyrimidin‐2‐ylamino) methyl] piperidine‐1‐carboxylate (CERC‐301), an orally bioavailable selective N‐methyl‐D‐aspartate (NMDA) receptor subunit 2B (GluN2B) antagonist, were characterized to develop a translational approach based on receptor occupancy (RO) to guide CERC‐301 dose selection in clinical trials of major depressive disorder. CERC‐301 demonstrated high‐binding affinity (Ki, 8.1 nmol L−1) specific to GluN2B with an IC50 of 3.6 nmol L−1 and no off‐target activity. CERC‐301 efficacy was demonstrated in the forced swim test with an efficacy dose (ED50) of 0.3–0.7 mg kg−1 (RO, 30–50%); increase in locomotor activity was observed at ED50 of 2 mg kg−1, corresponding to an RO of 75%. The predicted 50% RO concentration (Occ50) in humans was 400 nmol L−1, similar to that predicted for rat, dog, and monkey (300, 200, and 400 nmol L−1, respectively). Safety pharmacology and neurotoxicity studies raised no specific safety concerns. A first‐in‐human study in healthy males demonstrated a dose‐proportional pharmacokinetic profile, with Tmax of ~1 h and t1/2 of 12–17 h. Based on the preclinical and pharmacodynamic data, doses of ≥8 mg in humans are hypothesized to have an acceptable safety profile and result in clinically relevant peak plasma exposure.