2. Academic Validation
  3. MK-5172, a selective inhibitor of hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants

MK-5172, a selective inhibitor of hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants

  • Antimicrob Agents Chemother. 2012 Aug;56(8):4161-7. doi: 10.1128/AAC.00324-12.
Vincenzo Summa 1,  Steven W Ludmerer,  John A McCauley,  Christine Fandozzi,  Christine Burlein,  Giuliano Claudio,  Paul J Coleman,  Jillian M Dimuzio,  Marco Ferrara,  Marcello Di Filippo,  Adam T Gates,  Donald J Graham,  Steven Harper,  Daria J Hazuda,  Qian Huang,  Carolyn McHale,  Edith Monteagudo,  Vincenzo Pucci,  Michael Rowley,  Michael T Rudd,  Aileen Soriano,  Mark W Stahlhut,  Joseph P Vacca,  David B Olsen,  Nigel J Liverton,  Steven S Carroll
Affiliations

Affiliation

  • 1 Merck & Co. Inc., Whitehouse Station, New Jersey, USA.
PMID: 22615282 DOI: 10.1128/AAC.00324-12
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.

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