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
The effect of introducing hydrophobic groups onto the disaccharide portion of the mannopeptimycins has been examined. Under acid-catalyzed conditions dimethyl acetals and ketals react on the terminal mannose of the disaccharide moiety of mannopeptimycin-alpha and the cyclohexylalanyl analogue 2. The preferentially formed monofunctionalized 4,6-acetals and -ketals display potent antibacterial activities against Gram-positive microorganisms, including MRSA, PRSP, and VRE pathogens.
Subject(s)
Acetals/chemical synthesis , Anti-Bacterial Agents/chemical synthesis , Glycopeptides , Gram-Positive Bacteria/drug effects , Acetals/chemistry , Acetals/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Hydrophobic and Hydrophilic Interactions , Magnetic Resonance Spectroscopy , Microbial Sensitivity Tests , Spectrometry, Mass, Electrospray Ionization , Structure-Activity RelationshipABSTRACT
High-throughput screening and subsequent optimization led to the discovery of novel 3-oxazolidinedione-6-aryl-pyridinones exemplified by compound 2 as potent and selective EP3 antagonists with excellent pharmacokinetic properties. Compound 2 was orally active and showed robust in vivo activities in overactive bladder models. To address potential bioactivation liabilities of compound 2, further optimization resulted in compounds 9 and 10, which maintained excellent potency, selectivity, and pharmacokinetic properties and showed no bioactivation liability in glutathione trapping studies. These highly potent, selective, and orally active EP3 antagonists are excellent tool compounds for investigating and validating potential therapeutic benefits from selectively inhibiting the EP3 receptor.
ABSTRACT
Structural features of two weak inhibitors of the ZipA-FtsZ protein-protein interaction which were found to bind to overlapping but different areas of the key binding site were combined in one new series of carboxybiphenyl-indoles with improved inhibitory activity.