title: Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor.
abstract: A new class of HCV NS3/4a protease inhibitors containing a P2 to P4 macrocyclic constraint was designed using a molecular modeling-derived strategy. Building on the profile of previous clinical compounds and exploring the P2 and linker regions of the series allowed for optimization of broad genotype and mutant enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 15 (MK-5172), which is active against genotype 1-3 NS3/4a and clinically relevant mutant enzymes and has good plasma exposure and excellent liver exposure in multiple species.
authors.affiliation: Departments of Medicinal Chemistry, Drug Metabolism, and Molecular Modeling, IRBM, Merck Research Laboratories , Rome, Italy.
authors.forename: Steven
authors.initials: S
authors.lastname: Harper
authors.affiliation: Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: John A
authors.initials: JA
authors.lastname: McCauley
authors.affiliation: Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Rudd
authors.affiliation: Departments of Medicinal Chemistry, Drug Metabolism, and Molecular Modeling, IRBM, Merck Research Laboratories , Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Ferrara
authors.affiliation: Departments of Medicinal Chemistry, Drug Metabolism, and Molecular Modeling, IRBM, Merck Research Laboratories , Rome, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: DiFilippo
authors.affiliation: Departments of Medicinal Chemistry, Drug Metabolism, and Molecular Modeling, IRBM, Merck Research Laboratories , Rome, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Crescenzi
authors.affiliation: Departments of Medicinal Chemistry, Drug Metabolism, and Molecular Modeling, IRBM, Merck Research Laboratories , Rome, Italy.
authors.forename: Uwe
authors.initials: U
authors.lastname: Koch
authors.affiliation: Departments of Medicinal Chemistry, Drug Metabolism, and Molecular Modeling, IRBM, Merck Research Laboratories , Rome, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Petrocchi
authors.affiliation: Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: M Katharine
authors.initials: MK
authors.lastname: Holloway
authors.affiliation: Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: John W
authors.initials: JW
authors.lastname: Butcher
authors.affiliation: Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Romano
authors.affiliation: Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Bush
authors.affiliation: Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Kevin F
authors.initials: KF
authors.lastname: Gilbert
authors.affiliation: Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: McIntyre
authors.affiliation: Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Nguyen
authors.affiliation: Departments of Medicinal Chemistry, Drug Metabolism, and Molecular Modeling, IRBM, Merck Research Laboratories , Rome, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Nizi
authors.affiliation: Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Steven S
authors.initials: SS
authors.lastname: Carroll
authors.affiliation: Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Ludmerer
authors.affiliation: Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Christine
authors.initials: C
authors.lastname: Burlein
authors.affiliation: Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Jillian M
authors.initials: JM
authors.lastname: DiMuzio
authors.affiliation: Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Graham
authors.affiliation: Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: McHale
authors.affiliation: Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Stahlhut
authors.affiliation: Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: David B
authors.initials: DB
authors.lastname: Olsen
authors.affiliation: Departments of Medicinal Chemistry, Drug Metabolism, and Molecular Modeling, IRBM, Merck Research Laboratories , Rome, Italy.
authors.forename: Edith
authors.initials: E
authors.lastname: Monteagudo
authors.affiliation: Departments of Medicinal Chemistry, Drug Metabolism, and Molecular Modeling, IRBM, Merck Research Laboratories , Rome, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Cianetti
authors.affiliation: Departments of Medicinal Chemistry, Drug Metabolism, and Molecular Modeling, IRBM, Merck Research Laboratories , Rome, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Giuliano
authors.affiliation: Departments of Medicinal Chemistry, Drug Metabolism, and Molecular Modeling, IRBM, Merck Research Laboratories , Rome, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Pucci
authors.affiliation: Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Nicole
authors.initials: N
authors.lastname: Trainor
authors.affiliation: Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Fandozzi
authors.affiliation: Departments of Medicinal Chemistry, Drug Metabolism, and Molecular Modeling, IRBM, Merck Research Laboratories , Rome, Italy.
authors.forename: Michael
authors.initials: M
authors.lastname: Rowley
authors.affiliation: Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
authors.affiliation: Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
authors.affiliation: Departments of Medicinal Chemistry, Drug Metabolism, and Molecular Modeling, IRBM, Merck Research Laboratories , Rome, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Summa
authors.affiliation: Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Liverton
keywords: HCV; MK-5172; genotype 3a; hepatitis C; macrocycle; mutant enzymes