ABSTRACT
A series of potent anthranilic acid-based inhibitors of the hepatitis C NS5B polymerase has been identified. The inhibitors bind to a site on NS5B between the thumb and palm regions adjacent to the active site as determined by X-ray crystallography of the enzyme-inhibitor complex. Guided by both molecular modeling and traditional SAR, the enzyme activity of the initial hit was improved by approximately 100-fold, yielding a series of potent and selective NS5B inhibitors with IC50 values as low as 10 nM. These compounds were also inhibitors of the HCV replicon in cultured HUH7 cells.
Subject(s)
Antiviral Agents/chemical synthesis , Hepacivirus/drug effects , Viral Nonstructural Proteins/antagonists & inhibitors , ortho-Aminobenzoates/chemical synthesis , Allosteric Regulation , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Binding Sites , Cell Line , Crystallography, X-Ray , Hepacivirus/enzymology , Hepacivirus/genetics , Humans , Models, Molecular , Replicon , Structure-Activity Relationship , Viral Nonstructural Proteins/chemistry , Virus Replication/drug effects , ortho-Aminobenzoates/chemistry , ortho-Aminobenzoates/pharmacologyABSTRACT
Inhibitors of matrix metalloprotease (MMP)-13 and tumor necrosis factor-alpha converting enzyme (TACE) have been highly sought as potential therapeutic agents for the treatment of osteoarthritis and rheumatoid arthritis, respectively. This review focuses on the published literature on these inhibitors from 2001 to mid-2003. Significant advances have been reported in the design and synthesis of potent and selective inhibitors of MMP-13 using hydroxamic acid and non-hydroxamate zinc chelators on a variety of scaffolds. TACE inhibitors based on variations of known MMP inhibitors scaffolds and novel designs have been reported. Selectivity profiles for these inhibitors range from broad-spectrum to TACE-specific. Future clinical studies on these and other inhibitors will determine which MMP, or set of MMPs, must be inhibited for efficacy and long-term safety.
Subject(s)
Matrix Metalloproteinase Inhibitors , Metalloendopeptidases/antagonists & inhibitors , Protease Inhibitors/chemistry , Protease Inhibitors/chemical synthesis , ADAM Proteins , ADAM17 Protein , Animals , Arthritis, Rheumatoid/drug therapy , Chelating Agents , Drug Design , Humans , Hydroxamic Acids/chemical synthesis , Matrix Metalloproteinase 13 , Osteoarthritis/drug therapy , Protease Inhibitors/therapeutic use , Structure-Activity Relationship , ZincABSTRACT
Modification of alpha-biphenylsulfonamidocarboxylic acids led to potent and selective MMP-13 inhibitors. Compound 16 showed 100% oral bioavailability in rats and demonstrated >50% inhibition of bovine cartilage degradation at 10 ng/mL.
Subject(s)
Collagenases/metabolism , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/pharmacokinetics , Matrix Metalloproteinase Inhibitors , Osteoarthritis/drug therapy , Administration, Oral , Animals , Benzofurans/chemical synthesis , Benzofurans/chemistry , Collagenases/chemistry , Drug Evaluation, Preclinical , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Inhibitory Concentration 50 , Matrix Metalloproteinase 13 , Models, Molecular , Molecular Structure , Rats , Substrate SpecificityABSTRACT
A series of nonnucleoside, N-alpha-methylbenzyl-N'-arylthiourea analogs were identified which demonstrated selective activity against varicella-zoster virus (VZV) but were inactive against other human herpesviruses, including herpes simplex virus. Representative compounds had potent activity against VZV early-passage clinical isolates and an acyclovir-resistant isolate. Resistant viruses generated against one inhibitor were also resistant to other compounds in the series, suggesting that this group of related small molecules was acting on the same virus-specific target. Sequencing of the VZV ORF54 gene from two independently derived resistant viruses revealed mutations in ORF54 compared to the parental VZV strain Ellen sequence. Recombinant VZV in which the wild-type ORF54 sequence was replaced with the ORF54 gene from either of the resistant viruses became resistant to the series of inhibitor compounds. Treatment of VZV-infected cells with the inhibitor impaired morphogenesis of capsids. Inhibitor-treated cells lacked DNA-containing dense-core capsids in the nucleus, and only incomplete virions were present on the cell surface. These data suggest that the VZV-specific thiourea inhibitor series block virus replication by interfering with the function of the ORF54 protein and/or other proteins that interact with the ORF54 protein.
Subject(s)
Antiviral Agents/pharmacology , Benzamides/pharmacology , Herpesvirus 3, Human/drug effects , Thiourea/analogs & derivatives , Thiourea/pharmacology , Virus Replication/drug effects , Acyclovir/pharmacology , Amino Acid Sequence , Antiviral Agents/chemistry , Capsid/chemistry , Capsid/metabolism , Cell Line , Drug Resistance, Viral/genetics , Herpesvirus 3, Human/genetics , Herpesvirus 3, Human/pathogenicity , Humans , Microbial Sensitivity Tests/methods , Molecular Sequence Data , Mutation , Open Reading Frames/genetics , Thiourea/chemistry , Viral Plaque Assay , Viral Proteins/chemistry , Viral Proteins/genetics , Viral Proteins/metabolismABSTRACT
Bis-(aryl)thioureas were found to be potent and selective inhibitors of cytomegalovirus (CMV) in cultured HFF cells. Of these, the thiazole analogue 38 was investigated as a potential development candidate.
Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Cytomegalovirus/drug effects , Thiourea/analogs & derivatives , Thiourea/pharmacology , Acylation , Benzene Derivatives/chemistry , Benzene Derivatives/pharmacology , Cell Line , Herpesviridae/drug effects , Humans , Inhibitory Concentration 50 , Structure-Activity RelationshipABSTRACT
A series of highly potent thiourea inhibitors of cytomegalovirus (CMV) with improved stability properties was prepared and evaluated. Compound 29 inhibited the virus in cultured HFF cells with IC50 of 0.2 nM.