Discovery of MK-1220: A Macrocyclic Inhibitor of Hepatitis C Virus NS3/4A Protease with Improved Preclinical Plasma Exposure
ACS Medicinal Chemistry Letters2011Vol. 2(3), pp. 207–212
Citations Over TimeTop 10% of 2011 papers
Michael T. Rudd, John A. McCauley, John W. Butcher, Joseph J. Romano, Charles McIntyre, Kevin T. Nguyen, Kevin F. Gilbert, Kimberly J. Bush, M. Katharine Holloway, John Swestock, Bang-Lin Wan, Steven S. Carroll, Jillian DiMuzio, Donald J. Graham, Steven W. Ludmerer, Mark W. Stahlhut, Christine Fandozzi, Nicole Trainor, David B. Olsen, Joseph P. Vacca, Nigel J. Liverton
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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