ABSTRACT
With the goal of identifying inhibitors of hepatitis C virus (HCV) NS3/4a protease that are potent against a wide range of genotypes and clinically relevant mutant viruses, several subseries of macrocycles were investigated based on observations made during the discovery of MK-5172. Quinazolinone-containing macrocycles were identified as promising leads, and optimization for superior cross-genotype and mutant enzyme potency as well as rat liver and plasma concentrations following oral dosing, led to the development of MK-2748. Additional investigation of a series of bis-macrocycles containing a fused 18- and 15-membered ring system were also optimized for the same properties, leading to the discovery of MK-6325. Both compounds display the broad genotype and mutant potency necessary for clinical development as next-generation HCV NS3/4a protease inhibitors.
Subject(s)
Antiviral Agents/pharmacology , Hepacivirus/enzymology , Macrocyclic Compounds/pharmacology , Quinazolinones/pharmacology , Sulfones/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Crystallography, X-Ray , Drug Discovery , Hepacivirus/drug effects , Hepacivirus/genetics , Hepatitis C/drug therapy , Hepatitis C/virology , Humans , Macrocyclic Compounds/chemistry , Macrocyclic Compounds/pharmacokinetics , Models, Molecular , Mutation , Quinazolinones/chemistry , Quinazolinones/pharmacokinetics , Rats , Sulfones/pharmacokinetics , Viral Nonstructural Proteins/geneticsABSTRACT
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.
Subject(s)
Carrier Proteins/antagonists & inhibitors , Hepacivirus/enzymology , Macrocyclic Compounds/chemistry , Protease Inhibitors/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , 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/metabolismABSTRACT
A series of macrocyclic compounds containing 2-substituted-quinoline moieties have been discovered and shown to exhibit excellent HCV NS3/4a genotype 3a and genotype 1b R155K mutant activity while maintaining the high rat liver exposure. Cyclization of the 2-substituted quinoline substituent led to a series of tricyclic P2 compounds which also display superb gt3a potency.
Subject(s)
Carrier Proteins/antagonists & inhibitors , Hepacivirus/enzymology , Macrocyclic Compounds/chemistry , Protease Inhibitors/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Carrier Proteins/metabolism , Cyclization , Genotype , Half-Life , Hepacivirus/genetics , Intracellular Signaling Peptides and Proteins , Kinetics , Liver/metabolism , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/pharmacokinetics , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacokinetics , Quinolines/chemistry , Rats , Structure-Activity Relationship , Viral Nonstructural Proteins/metabolismABSTRACT
The nonstructural hepatitis B virus (HBV) protein HBx has an important role in HBV replication and in HBV-associated liver disease. Many activities have been linked to HBx expression; however, the molecular mechanisms underlying many of these activities are unknown. One proposed HBx function is the regulation of cytosolic calcium. We analyzed calcium levels in HepG2 cells that expressed HBx or replicating HBV, and we demonstrated that HBx, expressed in the absence of other HBV proteins or in the context of HBV replication, elevates cytosolic calcium. We linked this elevation of cytosolic calcium to the association of HBx with the mitochondrial permeability transition pore.
