ABSTRACT
A novel series of P3 oxo-modified macrocyclic hepatitis C virus NS3/4A serine protease inhibitor was designed, synthesized and biologically evaluated. The hydroxy-substituted inhibitor 10 demonstrated high potency in genotype 1a and 1b replicon and in the panel of HCV protease mutants. Interestingly, the t-butyl carbonate analog 9c, while not the most potent one in this series, exhibited a virtually flat potency profile in the panel of HCV protease mutants, thus providing opportunity for further optimization.
Subject(s)
Drug Discovery , Hepacivirus/drug effects , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Cyclopropanes , Hepacivirus/genetics , Humans , Hydroxylation , Inhibitory Concentration 50 , Isoindoles , Lactams/chemistry , Lactams/pharmacology , Lactams, Macrocyclic , Molecular Structure , Mutation , Proline/analogs & derivatives , Protease Inhibitors/chemistry , Sulfonamides/chemistry , Sulfonamides/pharmacologyABSTRACT
A novel series of cyclic urea-based CCR5 antagonists was designed aiming to resolve instability issue in the fasted simulated intestinal fluid (FSIF) associated with the acyclic urea moiety in 1. This class of CCR5 compounds demonstrated high antiviral activities against HIV-1 infection in both HOS and PBL assays. Further evaluation of these compounds indicated that 16-R not only substantially enhanced its stability, but also exhibited excellent pharmacokinetics properties.
