ABSTRACT
ABT-072 is a non-nucleoside HCV NS5B polymerase inhibitor that was discovered as part of a program to identify new direct-acting antivirals (DAAs) for the treatment of HCV infection. This compound was identified during a medicinal chemistry effort to improve on an original lead, inhibitor 1, which we described in a previous publication. Replacement of the amide linkage in 1 with a trans-olefin resulted in improved compound permeability and solubility and provided much better pharmacokinetic properties in preclinical species. Replacement of the dihydrouracil in 1 with an N-linked uracil provided better potency in the genotype 1 replicon assay. Results from phase 1 clinical studies supported once-daily oral dosing with ABT-072 in HCV infected patients. A phase 2 clinical study that combined ABT-072 with the HCV protease inhibitor ABT-450 provided a sustained virologic response at 24 weeks after dosing (SVR24) in 10 of 11 patients who received treatment.
Subject(s)
Cytosine/analogs & derivatives , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Hepacivirus/enzymology , Stilbenes/chemistry , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Administration, Oral , Biological Availability , Chemistry Techniques, Synthetic , Cytosine/chemical synthesis , Cytosine/chemistry , Cytosine/pharmacokinetics , Cytosine/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Humans , Permeability , Stereoisomerism , Sulfonamides/chemistry , Sulfonamides/pharmacokinetics , Tissue Distribution , Viral Nonstructural Proteins/chemistryABSTRACT
Research toward a next-generation HCV NS5A inhibitor has identified fluorobenzimidazole analogs that demonstrate potent, broad-genotype in vitro activity against HCV genotypes 1-6 replicons as well as HCV NS5A variants that are orders of magnitude less susceptible to inhibition by first-generation NS5A inhibitors in comparison to wild-type replicons. The fluorobenzimidazole inhibitors have improved pharmacokinetic properties in comparison to non-fluorinated benzimidazole analogs. Discovery of these inhibitors was facilitated by exploring SAR in a structurally simplified inhibitor series.
Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Hepacivirus/drug effects , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/pharmacokinetics , Benzimidazoles/pharmacokinetics , Dogs , Genotype , Halogenation , Hepacivirus/genetics , Hepacivirus/metabolism , Hepatitis C/drug therapy , Humans , Mice , Rats , Replicon/drug effects , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolismABSTRACT
The synthesis and structure-activity relationships of a novel aryl uracil series which contains a fused 5,6-bicyclic ring unit for HCV NS5B inhibition is described. Several analogs display replicon cell culture potencies in the low nanomolar range along with excellent rat pharmacokinetic values.
Subject(s)
Bridged Bicyclo Compounds/chemistry , Bridged Bicyclo Compounds/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Uracil/antagonists & inhibitors , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Bridged Bicyclo Compounds/chemical synthesis , Bridged Bicyclo Compounds/pharmacokinetics , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Hepacivirus/enzymology , RNA-Dependent RNA Polymerase/antagonists & inhibitors , RNA-Dependent RNA Polymerase/metabolism , Rats , Structure-Activity Relationship , Uracil/pharmacology , Viral Nonstructural Proteins/metabolismABSTRACT
A series of gem-dialkyl naphthalenone derivatives with varied alkyl substitutions were synthesized and evaluated according to their structure-activity relationship. This investigation led to the discovery of potent inhibitors of the hepatitis C virus at low nanomolar concentrations in both enzymatic and cell-based HCV genotype 1a assays.
Subject(s)
DNA-Directed RNA Polymerases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Hepacivirus/enzymology , Naphthalenes/pharmacology , Genotype , Hepacivirus/genetics , Structure-Activity RelationshipABSTRACT
Substituted N-alkyl-4-hydroxyquinolon-3-yl-benzothiadiazine sulfamides were investigated as inhibitors of genotype 1 HCV polymerase. Structure-activity relationship patterns for this class of compounds are discussed.
Subject(s)
Benzothiadiazines , Enzyme Inhibitors , Sulfonamides , Viral Nonstructural Proteins/antagonists & inhibitors , Benzothiadiazines/chemical synthesis , Benzothiadiazines/chemistry , Benzothiadiazines/pharmacology , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Molecular Structure , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Sulfonamides/pharmacology , Viral Nonstructural Proteins/chemistryABSTRACT
A series of non-nucleoside HCV NS5B polymerase inhibitors based on the N-1-benzyl or N-1-[3-methylbutyl]-4-hydroxy-1,8-naphthyridon-3-yl benzothiadiazine core substituted in the D-ring aromatic moiety have been prepared and evaluated. Aromatic substituents extending from position 7 of the D-ring exhibited excellent potency against both genotypes 1a and 1b.
Subject(s)
Benzothiadiazines/pharmacology , Enzyme Inhibitors/pharmacology , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Viral Nonstructural Proteins/antagonists & inhibitors , Virus Replication/drug effects , Benzothiadiazines/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Genotype , Hydrocarbons, Aromatic/chemistry , Inhibitory Concentration 50 , Naphthyridines/chemistry , Structure-Activity RelationshipABSTRACT
A series of non-amide-linked 6-substituted-2-naphthamidine urokinase plasminogen activator (uPA) inhibitors are described. These compounds possess excellent binding activities and selectivities with significantly improved pharmacokinetic profiles versus previously described amide-linked inhibitors.
Subject(s)
Naphthalenes/pharmacokinetics , Plasminogen Inactivators/pharmacokinetics , Urokinase-Type Plasminogen Activator/antagonists & inhibitors , Models, Molecular , Naphthalenes/chemistry , Plasminogen Inactivators/chemistry , Substrate SpecificityABSTRACT
Several 8-substituted 2-naphthamidine-based inhibitors of the serine protease urokinase plasminogen activator (uPA) are described. Direct attachment of five-membered saturated or unsaturated rings improved inhibitor performance; substitution with sulfones further improved binding profiles. Combination of these substituents or of previously described NH-linked heteroaromatic rings with 6-phenyl amide substituents provided further enhancements to potency and selectivity.
Subject(s)
Blood Proteins/chemistry , Naphthalenes/chemistry , Serine Proteinase Inhibitors/chemistry , Urokinase-Type Plasminogen Activator/antagonists & inhibitors , Blood Proteins/metabolism , Naphthalenes/metabolism , Serine Proteinase Inhibitors/metabolism , Urokinase-Type Plasminogen Activator/metabolismABSTRACT
The preparation and assessment of biological activity of 6-substituted 2-naphthamidine inhibitors of the serine protease urokinase plasminogen activator (uPA, or urokinase) is described. 2-Naphthamidine was chosen as a starting point based on synthetic considerations and on modeling of substituent vectors. Phenyl amides at the 6-position were found to improve binding; replacement of the amide with other two-atom linkers proved ineffective. The phenyl group itself is situated near the S1' subsite; substitutions off of the phenyl group accessed S1' and other distant binding regions. Three new points of interaction were defined and explored through ring substitution. A solvent-exposed salt bridge with the Asp60A carboxylate was formed using a 4-alkylamino group, improving affinity to K(i) = 40 nM. Inhibitors also accessed two hydrophobic regions. One interaction is characterized by a tight hydrophobic fit made with a small dimple largely defined by His57 and His99; a weaker, less specific interaction involves alkyl groups reaching into the broad prime-side protein binding region near Val41 and the Cys42-Cys58 disulfide, displacing water molecules and leading to small gains in activity. Many inhibitors accessed two of these three regions. Affinities range as low as K(i) = 6 nM, and many compounds had K(i) < 100 nM, while moderate to excellent selectivity was gained versus four of five members of a panel of relevant serine proteases. Also, some selectivity against trypsin was generated via the interaction with Asp60A. X-ray structures of many of these compounds were used to inform our inhibitor design and to increase our understanding of key interactions. In combination with our exploration of 8-substitution patterns, we have identified a number of novel binding interactions for uPA inhibitors.
Subject(s)
Amidines/chemical synthesis , Naphthalenes/chemical synthesis , Urokinase-Type Plasminogen Activator/antagonists & inhibitors , Amidines/chemistry , Amidines/pharmacology , Binding Sites , Crystallography, X-Ray , Humans , Models, Molecular , Molecular Structure , Naphthalenes/chemistry , Naphthalenes/pharmacology , Protein Binding , Solvents , Structure-Activity RelationshipABSTRACT
Farnesyltransferase inhibitors (FTIs) have been developed as potential anti-cancer agents due to their efficacy in blocking malignant growth in a variety of murine models of human tumors. To that end, we have developed a series of pyridone farnesyltransferase inhibitors with potent in vitro and cellular activity. The synthesis, SAR and biological properties of these compounds will be discussed.
Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Pyridones/chemical synthesis , Pyridones/pharmacology , Animals , Antineoplastic Agents/toxicity , Cell Division/drug effects , Cell Line, Tumor , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/toxicity , Farnesyltranstransferase , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
Urokinase type plasminogen activator (uPA) activates plasminogen to plasmin and is often associated with diseases where tissue remodeling is essential (e.g. cancer, macular degeneration, atherosclerosis). We discuss some of the mechanisms of uPA action in diseases, and evidence that some of the early uPA inhibitors can modulate the progression of these diseases. Recently, a number of research groups have discovered, with the aid of structure-based design, a new generation of uPA inhibitors. These inhibitors are much more potent and selective than their predecessors. We will review this progress here, and give particular attention to the structural rationale associated with these observed increases in potency and selectivity.