ABSTRACT
Hepatitis C (HCV) infection is a global health crisis leading to chronic liver disease. In our efforts towards a second generation HCV NS3 serine protease inhibitor with improved profile, we have undertaken SAR studies in various regions of Boceprevir including P2. Herein, we report the synthesis and structure-activity relationship studies of inhibitors with (S)-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid 2 as P2 substituent replacing the (1R,2S,5S)-6,6-dimethyl 3-azabicyclo[3.1.0]hexane-2-carboxylic acid. The systematic investigation led to the discovery of highly potent inhibitor 25 (K(i)( *)=7nM, EC(90)=30nM) with improved rat exposure of 2.56microM h.
Subject(s)
Antiviral Agents/chemistry , Proline/analogs & derivatives , Protease Inhibitors/chemistry , Quinolizines/chemistry , Sulfur Compounds/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacokinetics , Binding Sites , Computer Simulation , Humans , Proline/chemical synthesis , Proline/chemistry , Proline/pharmacokinetics , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacokinetics , Rats , Structure-Activity Relationship , Viral Nonstructural Proteins/metabolismABSTRACT
Hepatitis C virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, which affects more than 170 million people worldwide. Currently the only therapeutic regimens are subcutaneous interferon-alpha or polyethylene glycol (PEG)-interferon-alpha alone or in combination with oral ribavirin. Although combination therapy is reasonably successful with the majority of genotypes, its efficacy against the predominant genotype (genotype 1) is moderate at best, with only about 40% of the patients showing sustained virological response. Herein, the SAR leading to the discovery of 70 (SCH 503034), a novel, potent, selective, orally bioavailable NS3 protease inhibitor that has been advanced to clinical trials in human beings for the treatment of hepatitis C viral infections is described. X-ray structure of inhibitor 70 complexed with the NS3 protease and biological data are also discussed.
Subject(s)
Antiviral Agents/chemical synthesis , Hepacivirus/enzymology , Proline/analogs & derivatives , Viral Nonstructural Proteins/antagonists & inhibitors , Administration, Oral , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Area Under Curve , Binding Sites , Biological Availability , Crystallography, X-Ray , Dogs , Haplorhini , Molecular Structure , Proline/chemical synthesis , Proline/chemistry , Proline/pharmacokinetics , Rats , Structure-Activity Relationship , Tissue Distribution , Viral Nonstructural Proteins/chemistryABSTRACT
Introduction of various modified prolines at P(2) and optimization of the P(1) side chain led to the discovery of SCH6 (24, Table 2), a potent ketoamide inhibitor of the HCV NS3 serine protease. In addition to excellent enzyme potency (K(i)*= 3.8 nM), 24 was also found to be a potent inhibitor of HCV subgenomic RNA replication with IC(50) and IC(90) of 40 and 100 nM, respectively. Recently, antiviral activity of 24 was demonstrated with inhibition of the full-length genotype 2a HCV genome. In addition, 24 was found to restore the responsiveness of the interferon regulatory factor 3 (IRF-3) in cells containing HCV RNA replicons.
Subject(s)
Amides/chemistry , Amides/pharmacology , Genome, Viral/genetics , Hepacivirus/drug effects , Oligopeptides/chemistry , Oligopeptides/pharmacology , Serine Endopeptidases/metabolism , Animals , Haplorhini , Hepacivirus/enzymology , Hepacivirus/genetics , Models, Molecular , Molecular Structure , RNA, Viral/genetics , Rats , Serine Endopeptidases/chemistry , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/metabolismABSTRACT
As part of a detailed study, the syntheses, biological activities, and pharmacokinetic properties of hydroxylated analogues of the previously described broad spectrum antifungal agents, Sch 51048 (1), Sch 50001 (3), and Sch 50002 (4), are described. Based on an overall superior profile, one of the alcohols, Sch 56592 (2), was selected for clinical studies.
