ABSTRACT
EDP-239, a novel hepatitis C virus (HCV) inhibitor targeting nonstructural protein 5A (NS5A), has been investigated in vitro and in vivo EDP-239 is a potent, selective inhibitor with potency at picomolar to nanomolar concentrations against HCV genotypes 1 through 6. In the presence of human serum, the potency of EDP-239 was reduced by less than 4-fold. EDP-239 is additive to synergistic with other direct-acting antivirals (DAAs) or host-targeted antivirals (HTAs) in blocking HCV replication and suppresses the selection of resistance in vitro Furthermore, EDP-239 retains potency against known DAA- or HTA-resistant variants, with half-maximal effective concentrations (EC50s) equivalent to those for the wild type. In a phase I, single-ascending-dose, placebo-controlled clinical trial, EDP-239 demonstrated excellent pharmacokinetic properties that supported once daily dosing. A single 100-mg dose of EDP-239 resulted in reductions in HCV genotype 1a viral RNA of >3 log10 IU/ml within the first 48 h after dosing and reductions in genotype 1b viral RNA of >4-log10 IU/ml within 96 h. (This study has been registered at ClinicalTrials.gov under identifier NCT01856426.).
Subject(s)
Antiviral Agents/pharmacology , Benzimidazoles/pharmacology , Hepacivirus/drug effects , Hepatitis C, Chronic/drug therapy , Valine/analogs & derivatives , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/pharmacokinetics , Carbamates , Cell Line , Drug Evaluation, Preclinical/methods , Drug Resistance, Viral/drug effects , Drug Resistance, Viral/genetics , Drug Therapy, Combination , Female , Hepacivirus/genetics , Humans , Imidazoles/pharmacology , Male , Pyrrolidines , RNA, Viral/blood , Valine/pharmacology , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolism , Virus Replication/drug effectsABSTRACT
A bridging chemistry process was developed to form an ether bridge between 6-O and 11-O of erythromycin A via a tandem or stepwise palladium-catalyzed bis-pi-allylation. By applying this bridging process, new 6,11-O-bridged bicyclic ketolides (BBKs) were synthesized. These BBKs showed good antibacterial activities against the macrolide-susceptible strains as well as mef-resistant strains and served as a good core for further modifications to study the structure-activity relationship (SAR) and to overcome bacterial resistance. [reaction: see text]
ABSTRACT
Novel 4'-substituted 16-membered ring macrolides were synthesized by the cleavage of the mycarose sugar of tylosin and subsequent modification of 4'-hydroxyl group. This new class of macrolide antibiotics exhibited potent activity against some key erythromycin-resistant pathogens.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Tylosin/analogs & derivatives , Tylosin/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Drug Resistance, Bacterial , Erythromycin/pharmacology , Haemophilus influenzae/drug effects , Staphylococcus aureus/drug effects , Streptococcus pneumoniae/drug effects , Streptococcus pyogenes/drug effects , Tylosin/chemistry , Tylosin/pharmacologyABSTRACT
Building bridges: A feasible solid-phase synthesis of antiparallel n-, h-, and H-type DNA oligomers has been demonstrated. The oligomers possess a CH2 -bridged base-pair model that should be conformationally flexible, even after base pairing.
ABSTRACT
Cyclization instead of O-phosphorylation is the result of the reaction of the antiviral nucleoside anologue 1 with highly reactive phosphorylating agents. The formation of the novel polycyclic compound 2 shows that 1 has the Z configuration, which is important for the antiviral activity of 1 and related compounds.
