Discovery of MK-1220: A Macrocyclic Inhibitor of Hepatitis C Virus NS3/4A Protease with Improved Preclinical Plasma Exposure
Michael T. Rudd(United States Military Academy), John A. McCauley(United States Military Academy), John W. Butcher(United States Military Academy), Joseph J. Romano(United States Military Academy), Charles McIntyre(United States Military Academy), Kevin T. Nguyen(United States Military Academy), Kevin F. Gilbert(United States Military Academy), Kimberly J. Bush(United States Military Academy), M. Katharine Holloway(United States Military Academy), John Swestock(United States Military Academy), Bang-Lin Wan(United States Military Academy), Steven S. Carroll(United States Military Academy), Jillian DiMuzio(United States Military Academy), Donald J. Graham(United States Military Academy), Steven W. Ludmerer(United States Military Academy), Mark W. Stahlhut(United States Military Academy), Christine Fandozzi(United States Military Academy), Nicole Trainor(United States Military Academy), David B. Olsen(United States Military Academy), Joseph P. Vacca(United States Military Academy), Nigel J. Liverton(United States Military Academy)
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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.
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