ABSTRACT
Exploration of the P2 region by mimicking the proline motif found in BILN2061 resulted in the discovery of two series of potent HCV NS3/4A protease inhibitors. X-ray crystal structure of the ligand in contact with the NS3/4A protein and modulation of the quinoline heterocyclic region by structure based design and modeling allowed for the optimization of enzyme potency and cellular activity. This research led to the selection of clinical candidate IDX320 having good genotype coverage and pharmacokinetic properties in various species.
Subject(s)
Drug Discovery , Hepacivirus/drug effects , Macrocyclic Compounds/chemistry , Macrocyclic Compounds/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Haplorhini , Hepatocytes/enzymology , Humans , Inhibitory Concentration 50 , Mice , Microsomes, Liver/enzymology , Molecular Structure , Rats , Rats, Sprague-Dawley , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Viral Nonstructural Proteins/chemistryABSTRACT
We disclose here the synthesis of a series of macrocyclic HCV protease inhibitors, where the homoserine linked together the quinoline P2' motif and the macrocyclic moiety. These compounds exhibit potent inhibitory activity against HCV NS3/4A protease and replicon cell based assay. Their enzymatic and antiviral activities are modulated by substitutions on the quinoline P2' at position 8 by methyl and halogens and by small heterocycles at position 2. The in vitro structure activity relationship (SAR) studies and in vivo pharmacokinetic (PK) evaluations of selected compounds are described herein.
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Hepacivirus/drug effects , Homoserine/pharmacology , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/chemistry , Dose-Response Relationship, Drug , Hepacivirus/enzymology , Homoserine/chemical synthesis , Homoserine/chemistry , Microbial Sensitivity Tests , Molecular Structure , Serine Proteinase Inhibitors/chemistry , Structure-Activity Relationship , Viral Nonstructural Proteins/metabolismABSTRACT
Structural homology between thrombin inhibitors and the early tetrapeptide HCV protease inhibitor led to the bioisosteric replacement of the P2 proline by a 2,4-disubstituted azetidine within the macrocyclic ß-strand mimic. Molecular modeling guided the design of the series. This approach was validated by the excellent activity and selectivity in biochemical and cell based assays of this novel series and confirmed by the co-crystal structure of the inhibitor with the NS3/4A protein (PDB code: 4TYD).
Subject(s)
Azetidines/pharmacology , Drug Design , Serine Proteinase Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Azetidines/chemical synthesis , Azetidines/chemistry , Crystallography, X-Ray , Dose-Response Relationship, Drug , Models, Molecular , Molecular Structure , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/chemistry , Structure-Activity Relationship , Viral Nonstructural Proteins/metabolismABSTRACT
A new phenolic acid trimer was detected by coupled liquid chromatography/mass spectroscopy in alkali extracts of maize bran. The trimer was purified by preparative silica gel chromatography. The structure of the new compound was elucidated on the basis of 1D and 2D NMR and corresponded to a 4-O-8', 5'-5" dehydrotriferulic acid.
