title: 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.
authors.affiliation: Merck & Co. Inc., Whitehouse Station, New Jersey, USA.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Summa
authors.forename: Steven W
authors.initials: SW
authors.lastname: Ludmerer
authors.forename: John A
authors.initials: JA
authors.lastname: McCauley
authors.forename: Christine
authors.initials: C
authors.lastname: Fandozzi
authors.forename: Christine
authors.initials: C
authors.lastname: Burlein
authors.forename: Giuliano
authors.initials: G
authors.lastname: Claudio
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
authors.forename: Jillian M
authors.initials: JM
authors.lastname: Dimuzio
authors.forename: Marco
authors.initials: M
authors.lastname: Ferrara
authors.forename: Marcello
authors.initials: M
authors.lastname: Di Filippo
authors.forename: Adam T
authors.initials: AT
authors.lastname: Gates
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Graham
authors.forename: Steven
authors.initials: S
authors.lastname: Harper
authors.forename: Daria J
authors.initials: DJ
authors.lastname: Hazuda
authors.forename: Qian
authors.initials: Q
authors.lastname: Huang
authors.forename: Carolyn
authors.initials: C
authors.lastname: McHale
authors.forename: Edith
authors.initials: E
authors.lastname: Monteagudo
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Pucci
authors.forename: Michael
authors.initials: M
authors.lastname: Rowley
authors.forename: Michael T
authors.initials: MT
authors.lastname: Rudd
authors.forename: Aileen
authors.initials: A
authors.lastname: Soriano
authors.forename: Mark W
authors.initials: MW
authors.lastname: Stahlhut
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
authors.forename: David B
authors.initials: DB
authors.lastname: Olsen
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Liverton
authors.forename: Steven S
authors.initials: SS
authors.lastname: Carroll
mesh_terms: D000577:Amides; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D002219:Carbamates; D003521:Cyclopropanes; D004285:Dogs; D024882:Drug Resistance, Viral; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000821:virology; D008099:Liver / Q000187:drug effects; D002679:Pan troglodytes; D011480:Protease Inhibitors / Q000494:pharmacology*; D011810:Quinoxalines / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats; D013449:Sulfonamides; D019562:Viral Load / Q000187:drug effects; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; D047029:Lactams, Macrocyclic
chemical_list: D000577:Amides; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D011480:Protease Inhibitors; D011810:Quinoxalines; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C080106:NS4A protein, flavivirus; C578009:grazoprevir; D047029:Lactams, Macrocyclic