ABSTRACT
We have synthesized and evaluated a series of novel HCV NS3 protease inhibitors with various P4 capping groups, which include urea, carbamate, methoxy-carboxamide, cyclic carbamate and amide, pyruvic amide, oxamate, oxalamide and cyanoguanidine. Most of these compounds are remarkably potent, exhibiting single-digit to sub-nanomolar activity in the enzyme assay and cell-based replicon assay. Selected compounds were also evaluated in the protease-inhibitor-resistant mutant transient replicon assay, and they were found to show quite different potency profiles against a panel of HCV protease-inhibitor-resistant mutants.
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Hepacivirus/drug effects , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Amides/chemistry , Animals , Antiviral Agents/chemistry , Carbamates/chemistry , Dose-Response Relationship, Drug , Drug Resistance, Viral/genetics , Guanidines/chemistry , Hepacivirus/enzymology , Hepacivirus/genetics , Microbial Sensitivity Tests , Molecular Structure , Oxamic Acid/chemistry , Rats , Serine Proteinase Inhibitors/chemistry , Structure-Activity Relationship , Urea/chemistry , Viral Nonstructural Proteins/metabolismABSTRACT
We describe the synthesis and potency of a novel series of N-substituted 2-phenyl- and 2-methyl-2-phenyl-1,4-diaminobutane- based CCR5 antagonists. Compounds 7a and 12f were found to be potent in anti-HIV assays and bioavailable in the low-dose rat PK model.
Subject(s)
Anti-HIV Agents/chemical synthesis , CCR5 Receptor Antagonists , Putrescine/chemistry , Animals , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacokinetics , Anti-HIV Agents/pharmacology , Cell Line , Disease Models, Animal , HIV Infections/drug therapy , HIV-1/drug effects , Inhibitory Concentration 50 , Rats , Rats, Sprague-DawleyABSTRACT
We have synthesized and evaluated a new series of acyclic P4-benzoxaborole-based HCV NS3 protease inhibitors. Structure-activity relationships were investigated, leading to the identification of compounds 5g and 17 with low nanomolar potency in the enzymatic and cell-based replicon assay. The linker-truncated compound 5j was found to exhibit improved absorption and oral bioavailability in rats, suggesting that further reduction of molecular weight and polar surface area could result in improved drug-like properties of this novel series.
Subject(s)
Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
We disclose here a series of P4-benzoxaborole-substituted macrocyclic HCV protease inhibitors. These inhibitors are potent against HCV NS3 protease, their anti-HCV replicon potencies are largely impacted by substitutions on benzoxaborole ring system and P2∗ groups. P2∗ 2-thiazole-isoquinoline provides best replicon potency. The in vitro SAR studies and in vivo PK evaluations of selected compounds are described herein.
Subject(s)
Antiviral Agents/chemical synthesis , Hepacivirus/enzymology , Macrocyclic Compounds/chemistry , Protease Inhibitors/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Administration, Oral , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Isoquinolines/chemistry , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/pharmacokinetics , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacokinetics , Rats , Structure-Activity Relationship , Thiazoles/chemistry , Viral Nonstructural Proteins/metabolismABSTRACT
HCV NS3/4A serine protease is essential for the replication of the HCV virus and has been a clinically validated target. A series of HCV NS3/4A protease inhibitors containing a novel acylsulfamoyl benzoxaborole moiety at the P1' region was synthesized and evaluated. The resulting P1-P3 and P2-P4 macrocyclic inhibitors exhibited sub-nanomolar potency in the enzymatic assay and low nanomolar activity in the cell-based replicon assay. The in vivo PK evaluations of selected compounds are also described.
Subject(s)
Boron Compounds/chemistry , Hepacivirus/enzymology , Protease Inhibitors/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/metabolism , Animals , Boron Compounds/chemical synthesis , Boron Compounds/pharmacokinetics , Catalytic Domain , Hepacivirus/drug effects , Male , Models, Molecular , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacokinetics , Rats , Rats, Sprague-Dawley , Virus Replication/drug effectsABSTRACT
The macrocyclic urea 2, a byproduct in the synthesis of benzoxaborole 1, was identified to be a novel and potent HCV protease inhibitor. We further explored this motif by synthesizing additional urea-based inhibitors and by characterizing them in replicase HCV protease-resistant mutants assay. Several compounds, exemplified by 12, were found to be more potent in HCV replicon assays than leading second generation inhibitors such as danoprevir and TMC-435350. Additionally, following oral administration, inhibitor 12 was found in rat liver in significantly higher concentrations than those reported for both danoprevir and TMC-435350, suggesting that inhibitor 12 has the combination of anti-HCV and pharmacokinetic properties that warrants further development of this series.
Subject(s)
Antiviral Agents/chemical synthesis , Drug Resistance, Viral , Hepacivirus/drug effects , Serine Proteinase Inhibitors/chemical synthesis , Urea/analogs & derivatives , Urea/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Administration, Oral , Animals , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Hepacivirus/enzymology , Hepacivirus/genetics , Hydrophobic and Hydrophilic Interactions , Liver/metabolism , Mutation , Rats , Replicon/drug effects , Serine Proteinase Inhibitors/pharmacokinetics , Serine Proteinase Inhibitors/pharmacology , Structure-Activity Relationship , Urea/pharmacokinetics , Urea/pharmacology , Viral Nonstructural Proteins/geneticsABSTRACT
Diels-Alder reactions of vinylazepines with N-phenylmaleimide afforded exclusively the exo cycloadduct, while high endo stereoselectivity was observed, as previously reported, in analogous reactions of vinylpiperideines. This curious contrast was confirmed by X-ray analysis of cycloadducts not susceptible to epimerization. The stereoselectivity of Diels-Alder reactions of vinylazepines, vinylpiperideines, and vinylcycloalkenes exhibits surprising divergence depending on the detailed diene structure, and DFT calculations (Becke3LYP) were undertaken to shed light on these observations. The model calculations correctly predict the major stereoisomers in these reactions, though they tend to significantly underestimate the stereoselectivity. The results suggest some general considerations in predicting or controlling the stereochemistry of this class of Diels-Alder reactions.