1. Development of macrocyclic inhibitors of HCV NS3/4A protease with cyclic constrained P2-P4 linkers.
- Author
-
Rudd MT, McIntyre CJ, Romano JJ, Butcher JW, Holloway MK, Bush K, Nguyen KT, Gilbert KF, Lyle TA, Liverton NJ, Wan BL, Summa V, Harper S, Rowley M, Vacca JP, Carroll SS, Burlein C, DiMuzio JM, Gates A, Graham DJ, Huang Q, Ludmerer SW, McClain S, McHale C, Stahlhut M, Fandozzi C, Taylor A, Trainor N, Olsen DB, and McCauley JA
- Subjects
- Animals, Binding Sites, Carrier Proteins metabolism, Catalytic Domain, Cyclization, Genotype, Half-Life, Hepacivirus genetics, Intracellular Signaling Peptides and Proteins, Kinetics, Liver metabolism, Macrocyclic Compounds chemical synthesis, Macrocyclic Compounds pharmacokinetics, Molecular Docking Simulation, Mutation, Protease Inhibitors chemical synthesis, Protease Inhibitors pharmacokinetics, Rats, Structure-Activity Relationship, Viral Nonstructural Proteins metabolism, Carrier Proteins antagonists & inhibitors, Hepacivirus enzymology, Macrocyclic Compounds chemistry, Protease Inhibitors chemistry, Viral Nonstructural Proteins antagonists & inhibitors
- Abstract
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 R155K, A156T, A156V, and D168V 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., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF