Bioorganic and Medicinal Chemistry Letters p. 7207 - 7213 (2012)
Update date:2022-08-05
Topics:
Rudd, Michael T.
McIntyre, Charles J.
Romano, Joseph J.
Butcher, John W.
Holloway, M. Katharine
Bush, Kimberly
Nguyen, Kevin T.
Gilbert, Kevin F.
Lyle, Terry A.
Liverton, Nigel J.
Wan, Bang-Lin
Summa, Vincenzo
Harper, Steven
Rowley, Michael
Vacca, Joseph P.
Carroll, Steven S.
Burlein, Christine
Dimuzio, Jillian M.
Gates, Adam
Graham, Donald J.
Huang, Qian
Ludmerer, Steven W.
McClain, Stephanie
McHale, Carolyn
Stahlhut, Mark
Fandozzi, Christine
Taylor, Anne
Trainor, Nicole
Olsen, David B.
McCauley, John A.
A series of macrocyclic compounds containing a cyclic constraint in the P2-P4 linker region have been discovered and shown to exhibit excellent HCV NS3/4a genotype 3a and genotype 1b R155 K, A156T, A156 V, and D168 V mutant activity while maintaining high rat liver exposure. The effect of the constraint is most dramatic against gt 1b A156 mutants where ~20-fold improvements in potency are achieved by introduction of a variety of ring systems into the P2-P4 linker.
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