Discovery of MK-1220: A Macrocyclic Inhibitor of Hepatitis C Virus NS3/4A Protease with Improved Preclinical Plasma Exposure.

Autor: Rudd MT; Departments of Medicinal Chemistry, Molecular Systems, Antiviral Research, and Drug Metabolism, Merck Research Laboratories , West Point, Pennsylvania 19486, United States., McCauley JA; Departments of Medicinal Chemistry, Molecular Systems, Antiviral Research, and Drug Metabolism, Merck Research Laboratories , West Point, Pennsylvania 19486, United States., Butcher JW; Departments of Medicinal Chemistry, Molecular Systems, Antiviral Research, and Drug Metabolism, Merck Research Laboratories , West Point, Pennsylvania 19486, United States., Romano JJ; Departments of Medicinal Chemistry, Molecular Systems, Antiviral Research, and Drug Metabolism, Merck Research Laboratories , West Point, Pennsylvania 19486, United States., McIntyre CJ; Departments of Medicinal Chemistry, Molecular Systems, Antiviral Research, and Drug Metabolism, Merck Research Laboratories , West Point, Pennsylvania 19486, United States., Nguyen KT; Departments of Medicinal Chemistry, Molecular Systems, Antiviral Research, and Drug Metabolism, Merck Research Laboratories , West Point, Pennsylvania 19486, United States., Gilbert KF; Departments of Medicinal Chemistry, Molecular Systems, Antiviral Research, and Drug Metabolism, Merck Research Laboratories , West Point, Pennsylvania 19486, United States., Bush KJ; Departments of Medicinal Chemistry, Molecular Systems, Antiviral Research, and Drug Metabolism, Merck Research Laboratories , West Point, Pennsylvania 19486, United States., Holloway MK; Departments of Medicinal Chemistry, Molecular Systems, Antiviral Research, and Drug Metabolism, Merck Research Laboratories , West Point, Pennsylvania 19486, United States., Swestock J; Departments of Medicinal Chemistry, Molecular Systems, Antiviral Research, and Drug Metabolism, Merck Research Laboratories , West Point, Pennsylvania 19486, United States., Wan BL; Departments of Medicinal Chemistry, Molecular Systems, Antiviral Research, and Drug Metabolism, Merck Research Laboratories , West Point, Pennsylvania 19486, United States., Carroll SS; Departments of Medicinal Chemistry, Molecular Systems, Antiviral Research, and Drug Metabolism, Merck Research Laboratories , West Point, Pennsylvania 19486, United States., DiMuzio JM; Departments of Medicinal Chemistry, Molecular Systems, Antiviral Research, and Drug Metabolism, Merck Research Laboratories , West Point, Pennsylvania 19486, United States., Graham DJ; Departments of Medicinal Chemistry, Molecular Systems, Antiviral Research, and Drug Metabolism, Merck Research Laboratories , West Point, Pennsylvania 19486, United States., Ludmerer SW; Departments of Medicinal Chemistry, Molecular Systems, Antiviral Research, and Drug Metabolism, Merck Research Laboratories , West Point, Pennsylvania 19486, United States., Stahlhut MW; Departments of Medicinal Chemistry, Molecular Systems, Antiviral Research, and Drug Metabolism, Merck Research Laboratories , West Point, Pennsylvania 19486, United States., Fandozzi CM; Departments of Medicinal Chemistry, Molecular Systems, Antiviral Research, and Drug Metabolism, Merck Research Laboratories , West Point, Pennsylvania 19486, United States., Trainor N; Departments of Medicinal Chemistry, Molecular Systems, Antiviral Research, and Drug Metabolism, Merck Research Laboratories , West Point, Pennsylvania 19486, United States., Olsen DB; Departments of Medicinal Chemistry, Molecular Systems, Antiviral Research, and Drug Metabolism, Merck Research Laboratories , West Point, Pennsylvania 19486, United States., Vacca JP; Departments of Medicinal Chemistry, Molecular Systems, Antiviral Research, and Drug Metabolism, Merck Research Laboratories , West Point, Pennsylvania 19486, United States., Liverton NJ; Departments of Medicinal Chemistry, Molecular Systems, Antiviral Research, and Drug Metabolism, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
Jazyk: angličtina
Zdroj: ACS medicinal chemistry letters [ACS Med Chem Lett] 2011 Jan 12; Vol. 2 (3), pp. 207-12. Date of Electronic Publication: 2011 Jan 12 (Print Publication: 2011).
DOI: 10.1021/ml1002426
Abstrakt: 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.
Databáze: MEDLINE