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Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor.
Harper, Steven; McCauley, John A; Rudd, Michael T; Ferrara, Marco; DiFilippo, Marcello; Crescenzi, Benedetta; Koch, Uwe; Petrocchi, Alessia; Holloway, M Katharine; Butcher, John W; Romano, Joseph J; Bush, Kimberly J; Gilbert, Kevin F; McIntyre, Charles J; Nguyen, Kevin T; Nizi, Emanuela; Carroll, Steven S; Ludmerer, Steven W; Burlein, Christine; DiMuzio, Jillian M; Graham, Donald J; McHale, Carolyn M; Stahlhut, Mark W; Olsen, David B; Monteagudo, Edith; Cianetti, Simona; Giuliano, Claudio; Pucci, Vincenzo; Trainor, Nicole; Fandozzi, Christine M; Rowley, Michael; Coleman, Paul J; Vacca, Joseph P; Summa, Vincenzo; Liverton, Nigel J.
Affiliation
  • Harper S; Departments of Medicinal Chemistry, Drug Metabolism, and Molecular Modeling, IRBM, Merck Research Laboratories , Rome, Italy.
  • McCauley JA; Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
  • Rudd MT; Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
  • Ferrara M; Departments of Medicinal Chemistry, Drug Metabolism, and Molecular Modeling, IRBM, Merck Research Laboratories , Rome, Italy.
  • DiFilippo M; Departments of Medicinal Chemistry, Drug Metabolism, and Molecular Modeling, IRBM, Merck Research Laboratories , Rome, Italy.
  • Crescenzi B; Departments of Medicinal Chemistry, Drug Metabolism, and Molecular Modeling, IRBM, Merck Research Laboratories , Rome, Italy.
  • Koch U; Departments of Medicinal Chemistry, Drug Metabolism, and Molecular Modeling, IRBM, Merck Research Laboratories , Rome, Italy.
  • Petrocchi A; Departments of Medicinal Chemistry, Drug Metabolism, and Molecular Modeling, IRBM, Merck Research Laboratories , Rome, Italy.
  • Holloway MK; Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
  • Butcher JW; Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
  • Romano JJ; Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
  • Bush KJ; Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
  • Gilbert KF; Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
  • McIntyre CJ; Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
  • Nguyen KT; Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
  • Nizi E; Departments of Medicinal Chemistry, Drug Metabolism, and Molecular Modeling, IRBM, Merck Research Laboratories , Rome, Italy.
  • Carroll SS; Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
  • Ludmerer SW; Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
  • Burlein C; Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
  • DiMuzio JM; Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
  • Graham DJ; Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
  • McHale CM; Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
  • Stahlhut MW; Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
  • Olsen DB; Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
  • Monteagudo E; Departments of Medicinal Chemistry, Drug Metabolism, and Molecular Modeling, IRBM, Merck Research Laboratories , Rome, Italy.
  • Cianetti S; Departments of Medicinal Chemistry, Drug Metabolism, and Molecular Modeling, IRBM, Merck Research Laboratories , Rome, Italy.
  • Giuliano C; Departments of Medicinal Chemistry, Drug Metabolism, and Molecular Modeling, IRBM, Merck Research Laboratories , Rome, Italy.
  • Pucci V; Departments of Medicinal Chemistry, Drug Metabolism, and Molecular Modeling, IRBM, Merck Research Laboratories , Rome, Italy.
  • Trainor N; Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
  • Fandozzi CM; Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
  • Rowley M; Departments of Medicinal Chemistry, Drug Metabolism, and Molecular Modeling, IRBM, Merck Research Laboratories , Rome, Italy.
  • Coleman PJ; Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
  • Vacca JP; Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
  • Summa V; Departments of Medicinal Chemistry, Drug Metabolism, and Molecular Modeling, IRBM, Merck Research Laboratories , Rome, Italy.
  • Liverton NJ; Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
ACS Med Chem Lett ; 3(4): 332-6, 2012 Apr 12.
Article in En | MEDLINE | ID: mdl-24900473
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: ACS Med Chem Lett Year: 2012 Document type: Article
Fulltext
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Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: ACS Med Chem Lett Year: 2012 Document type: Article