ABSTRACT
HCV infection affects more than 170 million people worldwide and many of those patients will reach the end stage complications of the disease which include hepatocarcinoma and liver failure. The success rate for treatment of patients infected with genotype-1 is about 40%. Therefore, novel treatments are needed to combat the infection. The HCV NS3 protease inhibitor Boceprevir (1) was reported by our research group and efforts continue for the discovery of more potent compounds with improved pharmacokinetic profiles. A new series of HCV NS3 protease inhibitors having a cyclic sulfone P3-cap have been discovered. Compounds 43 and 44 showed K(i)* values in the single-digit nM range and their cellular potency was improved by 10-fold compared to 1. The pharmacokinetic profiles of 43 and 44 in rats and monkeys were also improved to achieve higher plasma levels after oral administration.
Subject(s)
Hepacivirus/enzymology , Oligopeptides/chemical synthesis , Serine Proteinase Inhibitors/chemical synthesis , Sulfones/chemical synthesis , Administration, Oral , Animals , Crystallography, X-Ray , Haplorhini , Models, Molecular , Oligopeptides/pharmacokinetics , Oligopeptides/pharmacology , Rats , Serine Proteinase Inhibitors/pharmacokinetics , Serine Proteinase Inhibitors/pharmacology , Stereoisomerism , Structure-Activity Relationship , Sulfones/pharmacokinetics , Sulfones/pharmacologyABSTRACT
The structures of both native and S139A holo-HCV NS3/4A protease domain were solved to high resolution. Subsequently, structures were determined for a series of ketoamide inhibitors in complex with the protease. The changes in the inhibitor potency were correlated with changes in the buried surface area upon binding the inhibitor to the active site. The largest contributions to the binding energy arise from the hydrophobic interactions of the P1 and P2 groups as they bind to the S1 and S2 pockets. This correlation of the changes in potency with increased buried surface area contributed directly to the design of a potent tripeptide inhibitor of the HCV NS3/4A protease, which is currently in clinical trials.
Subject(s)
Hepacivirus/enzymology , Proline/analogs & derivatives , Protease Inhibitors/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Models, Molecular , Molecular Structure , Proline/chemistryABSTRACT
The structures of both the native holo-HCV NS3/4A protease domain and the protease domain with a serine 139 to alanine (S139A) mutation were solved to high resolution. Subsequently, structures were determined for a series of ketoamide inhibitors in complex with the protease. The changes in the inhibitor potency were correlated with changes in the buried surface area upon binding the inhibitor to the active site. The largest contribution to the binding energy arises from the hydrophobic interactions of the P1 and P2 groups as they bind to the S1 and S2 pockets [the numbering of the subsites is as defined in Berger, A.; Schechter, I. Philos. Trans. R. Soc. London, Ser. B 1970, 257, 249-264]. This correlation of the changes in potency with increased buried surface area contributed directly to the design of a potent tripeptide inhibitor of the HCV NS3/4A protease that is currently in clinical trials.
Subject(s)
Antiviral Agents/chemical synthesis , Carrier Proteins/antagonists & inhibitors , Carrier Proteins/chemistry , Hepacivirus/enzymology , Proline/analogs & derivatives , Serine Proteinase Inhibitors/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/chemistry , Viral Proteins/antagonists & inhibitors , Viral Proteins/chemistry , Antiviral Agents/chemistry , Binding Sites , Crystallography, X-Ray , Intracellular Signaling Peptides and Proteins , Models, Molecular , Proline/chemical synthesis , Proline/chemistry , Protein Conformation , Stereoisomerism , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Antifungal Agents/pharmacology , Chemistry, Pharmaceutical/methods , Triazoles/chemistry , Triazoles/chemical synthesis , Triazoles/pharmacology , Alcohols , Animals , Antifungal Agents/chemistry , Aspergillosis/drug therapy , Candidiasis/drug therapy , Dose-Response Relationship, Drug , Drug Design , Drug Evaluation, Preclinical , Haplorhini , Humans , Immunosuppressive Agents/pharmacology , Mice , Models, Chemical , Time Factors , Triazoles/pharmacokineticsABSTRACT
The four 2,2,5-regioisomer counterparts of SCH 51048 were synthesized and evaluated. As with the parent series, only the two cis isomers possessed any in vitro activity, and only the activity of the isomer with the R-configuration at the tetrahydrofuran 2-carbon was significant. The activity data suggests that oxygen at only one of the two possible ring positions benzylic to the difluorobenzene participates usefully in active site binding.
