ABSTRACT
A series of benzo[d]isothiazole-1,1-dioxides were designed and evaluated as inhibitors of HCV polymerase NS5B. Structure-based design led to the incorporation of a high affinity methyl sulfonamide group. Structure-activity relationship (SAR) studies of this series revealed analogues with submicromolar potencies in the HCV replicon assay and moderate pharmacokinetic properties. SAR studies combined with structure based drug design focused on the sulfonamide region led to a novel and potent cyclic analogue.
Subject(s)
Antiviral Agents/chemical synthesis , Hepacivirus/drug effects , Thiazoles/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Binding Sites , Crystallography, X-Ray , Haplorhini , Rats , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/pharmacokinetics , Viral Nonstructural Proteins/metabolismABSTRACT
Benzothiazine-substituted tetramic acids were discovered as highly potent non-nucleoside inhibitors of HCV NS5B polymerase. X-ray crystallography studies confirmed the binding mode of these inhibitors with HCV NS5B polymerase. Rational optimization of time dependent inactivation of CYP 3A4 and clearance was accomplished by incorporation of electron-withdrawing groups to the benzothiazine core.
Subject(s)
Antiviral Agents/chemical synthesis , Hepacivirus/drug effects , Pyrrolidinones/chemistry , Thiazines/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Binding Sites , Crystallography, X-Ray , Pyrrolidinones/chemical synthesis , Pyrrolidinones/pharmacokinetics , Rats , Structure-Activity Relationship , Viral Nonstructural Proteins/metabolismABSTRACT
A new series of benzothiazine-substituted quinolinediones were evaluated as inhibitors of HCV polymerase NS5B. SAR studies on this series revealed a methyl sulfonamide group as a high affinity feature. Analogues with this group showed submicromolar potencies in the HCV cell based replicon assay. Pharmacokinetic and toxicology studies were also performed on a selected compound (34) to evaluate in vivo properties of this new class of inhibitors of HCV NS5B polymerase.
Subject(s)
Antiviral Agents/chemistry , DNA-Directed RNA Polymerases/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Hepacivirus/drug effects , Quinolines/chemistry , Quinolones/chemistry , Thiazines/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacokinetics , Computer Simulation , Crystallography, X-Ray , DNA-Directed RNA Polymerases/metabolism , Dogs , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Humans , Quinolines/chemical synthesis , Quinolines/pharmacokinetics , Quinolones/chemical synthesis , Quinolones/pharmacology , Rats , Structure-Activity Relationship , Thiazines/chemical synthesis , Thiazines/pharmacology , Viral Nonstructural Proteins/metabolism , Virus Replication/drug effectsABSTRACT
The N-2 position of pyridazinone 1, a potent HIV-1 NNRTI that has limited aqueous solubility, was derivatized into a series of hydroxymethyl esters and carbonates as well as one phosphate. The derivatives served as prodrugs to effectively deliver 1 to rat plasma upon oral treatment at 50 mpk. Increases of 4.3- to 8.6-fold in 24-hour exposure of 1 (over that of parent) were observed while the prodrugs and the hydroxymethyl adduct 2 were undetectable.
Subject(s)
HIV Reverse Transcriptase/chemistry , HIV-1/enzymology , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/pharmacokinetics , Administration, Oral , Animals , Biological Availability , Carbonates/chemistry , Chemistry, Pharmaceutical/methods , Drug Design , Esters/chemistry , Hydrogen-Ion Concentration , Models, Chemical , Prodrugs/chemistry , Rats , SolubilityABSTRACT
A series of benzyl pyridazinones were evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Several members of this series showed good activity against the wild-type virus and NNRTI-resistant viruses. The binding of inhibitor 5a to HIV-RT was analyzed by surface plasmon resonance spectroscopy. Pharmacokinetic studies of 5a in rat and dog demonstrated that this compound has good oral bioavailability in animal species. The crystal structure of a complex between HIV-RT and inhibitor 4c is also described.
Subject(s)
HIV Reverse Transcriptase/antagonists & inhibitors , Pyridazines , Reverse Transcriptase Inhibitors , Animals , Dogs , Drug Resistance, Viral/drug effects , Inhibitory Concentration 50 , Molecular Structure , Pyridazines/chemical synthesis , Pyridazines/chemistry , Pyridazines/pharmacology , Rats , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
Novel non-nucleoside inhibitors of HIV-RT that contain pyridazinone isosteres were prepared, and a series of triazolinones were found to be potent inhibitors of HIV replication. These compounds were active against several NNRTI-resistant virus strains. Pharmacokinetic studies indicated that inhibitor 7e has good bioavailability in rats. Several fragments of inhibitor 7c were prepared, and the binding of these compounds to HIV-RT was analyzed by surface plasmon resonance spectroscopy.
Subject(s)
Anti-HIV Agents , Pyridazines , Reverse Transcriptase Inhibitors , Triazoles , Animals , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacokinetics , Anti-HIV Agents/pharmacology , Combinatorial Chemistry Techniques , Drug Resistance, Viral/drug effects , Molecular Structure , Pyridazines/chemical synthesis , Pyridazines/chemistry , Pyridazines/pharmacokinetics , Pyridazines/pharmacology , Rats , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/pharmacology , Structure-Activity Relationship , Surface Plasmon Resonance , Triazoles/chemical synthesis , Triazoles/chemistry , Triazoles/pharmacokinetics , Triazoles/pharmacologyABSTRACT
2-Piperidones were prepared bearing heptanoic acid or a thioether heptanoic acid at the 1-position as well as appropriately substituted at the 6-position to mimic the structure of prostaglandins. The stereochemical purity at the 6-position was determined to be 95% ee for an advanced synthetic intermediate. The 2-piperidones were identified as potent agonists at the EP4 prostanoid receptor. They displayed a high affinity (Ki 5-130 nM) at EP4 and subtype selectivity.
Subject(s)
Lactams/pharmacology , Piperidones/pharmacology , Receptors, Prostaglandin E/agonists , Lactams/chemistry , Ligands , Piperidones/chemistry , Receptors, Prostaglandin E, EP4 SubtypeABSTRACT
Two distinct synthetic schemes were applied to access heteroatom-containing alpha-chain lactams or lactams terminated as aryl acids. The latter lactams were devised using a pharmacophore for EP(4) receptor activity. gamma-Lactams were characterized for their prostanoid EP receptor affinities and EP(4) activity and found to be selective for the EP(2) and EP(4) receptors or selective for the EP(4) subtype. Benzoic acid 17 displayed enhanced in vivo exposure relative to 3.
Subject(s)
Benzoates/chemical synthesis , Lactams/chemical synthesis , Pyrrolidines/chemical synthesis , Receptors, Prostaglandin E/agonists , Animals , Benzoates/pharmacokinetics , Benzoates/pharmacology , Blood Proteins/metabolism , Half-Life , Humans , Lactams/pharmacokinetics , Lactams/pharmacology , Models, Molecular , Molecular Conformation , Monte Carlo Method , Oxidation-Reduction , Protein Binding , Pyrrolidines/pharmacokinetics , Pyrrolidines/pharmacology , Rats , Receptors, Prostaglandin E/metabolism , Receptors, Prostaglandin E, EP2 Subtype , Receptors, Prostaglandin E, EP4 Subtype , Structure-Activity RelationshipABSTRACT
A series of 7-[(5R)-substituted 2-oxo-1-pyrrolidinyl]-heptanoic acids were prepared, their isomeric purity determined, and pharmacologically evaluated. Lactams with affinity for the EP(4) receptor displayed agonist behavior. The lower side-chain of the lactam template could be substituted to afford ligands (e.g., 17, 24, 30, 31, and 33) of high potency and greater than 1000-fold affinity for EP(4) versus the other EP prostanoid receptors.
