title: Discovery of MK-1220: A Macrocyclic Inhibitor of Hepatitis C Virus NS3/4A Protease with Improved Preclinical Plasma Exposure.
abstract: The discovery of MK-1220 is reported along with the development of a series of HCV NS3/4A protease inhibitors containing a P2 to P4 macrocyclic constraint with improved preclinical pharmacokinetics. Optimization of the P2 heterocycle substitution pattern as well as the P3 amino acid led to compounds with greatly improved plasma exposure following oral dosing in both rats and dogs while maintaining excellent enzyme potency and cellular activity. These studies led to the identification of MK-1220.
authors.affiliation: Departments of Medicinal Chemistry, Molecular Systems, Antiviral Research, and Drug Metabolism, 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, Molecular Systems, Antiviral Research, and Drug Metabolism, 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, Molecular Systems, Antiviral Research, and Drug Metabolism, 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, Molecular Systems, Antiviral Research, and Drug Metabolism, 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, Molecular Systems, Antiviral Research, and Drug Metabolism, 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, Molecular Systems, Antiviral Research, and Drug Metabolism, 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, Molecular Systems, Antiviral Research, and Drug Metabolism, 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, Molecular Systems, Antiviral Research, and Drug Metabolism, 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, Molecular Systems, Antiviral Research, and Drug Metabolism, 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, Molecular Systems, Antiviral Research, and Drug Metabolism, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: John
authors.initials: J
authors.lastname: Swestock
authors.affiliation: Departments of Medicinal Chemistry, Molecular Systems, Antiviral Research, and Drug Metabolism, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Bang-Lin
authors.initials: BL
authors.lastname: Wan
authors.affiliation: Departments of Medicinal Chemistry, Molecular Systems, Antiviral Research, and Drug Metabolism, 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, Molecular Systems, Antiviral Research, and Drug Metabolism, 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, Molecular Systems, Antiviral Research, and Drug Metabolism, 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, Molecular Systems, Antiviral Research, and Drug Metabolism, 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, Molecular Systems, Antiviral Research, and Drug Metabolism, 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, Molecular Systems, Antiviral Research, and Drug Metabolism, 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, Molecular Systems, Antiviral Research, and Drug Metabolism, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Nicole
authors.initials: N
authors.lastname: Trainor
authors.affiliation: Departments of Medicinal Chemistry, Molecular Systems, Antiviral Research, and Drug Metabolism, 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, Molecular Systems, Antiviral Research, and Drug Metabolism, 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, Molecular Systems, Antiviral Research, and Drug Metabolism, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Liverton
keywords: HCV; Hepatitis C; NS3/4A; macrocycle; ring-closing metathesis