ABSTRACT
VX-787 is a first in class, orally bioavailable compound that offers unparalleled potential for the treatment of pandemic and seasonal influenza. As a part of our routine SAR exploration, carboxylic acid isosteres of VX-787 were prepared and tested against influenza A. It was found that the negative charge is important for maintaining potency and selectivity relative to kinase targets. Neutral carboxylic acid replacements generally resulted in compounds that were significantly less potent and less selective relative to the charged species.
Subject(s)
Antiviral Agents/pharmacology , Aza Compounds/pharmacology , Indoles/pharmacology , Influenza A virus/drug effects , Protein Kinase Inhibitors/pharmacology , Viral Proteins/antagonists & inhibitors , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Aza Compounds/chemistry , Carboxylic Acids/chemistry , Dose-Response Relationship, Drug , Indoles/chemical synthesis , Indoles/chemistry , Influenza A virus/enzymology , Microbial Sensitivity Tests , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyridines , Pyrimidines , Pyrroles , Structure-Activity Relationship , Viral Proteins/metabolismABSTRACT
A series of 2,6-disubstituted aminoalkoxypyrimidine carboxamides (AAPCs) with potent inhibition of bacterial NAD(+)-dependent DNA ligase was discovered through the use of structure-guided design. Two subsites in the NAD(+)-binding pocket were explored to modulate enzyme inhibitory potency: a hydrophobic selectivity region was explored through a series of 2-alkoxy substituents while the sugar (ribose) binding region of NAD(+) was explored via 6-alkoxy substituents.
Subject(s)
Amides/chemistry , Anti-Bacterial Agents/chemical synthesis , Bacterial Proteins/antagonists & inhibitors , DNA Ligases/antagonists & inhibitors , Drug Design , Enzyme Inhibitors/chemical synthesis , Amides/chemical synthesis , Amides/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/metabolism , Binding Sites , Catalytic Domain , Computer Simulation , Crystallography, X-Ray , DNA Ligase ATP , DNA Ligases/metabolism , Enterococcus faecalis/drug effects , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Microbial Sensitivity Tests , NAD/metabolism , Pyrimidines/chemistry , Structure-Activity RelationshipABSTRACT
In our efforts to develop novel small-molecule inhibitors for the treatment of influenza, we utilized molecular modeling and the X-ray crystal structure of the PB2 subunit of the influenza polymerase to optimize a series of acyclic ß-amino acid inhibitors, highlighted by compound 4. Compound 4 showed good oral exposure in both rat and mouse. More importantly, it showed strong potency versus multiple influenza-A strains, including pandemic 2009 H1N1 and avian H5N1 strains and showed a strong efficacy profile in a mouse influenza model even when treatment was initiated 48 h after infection. Compound 4 offers good oral bioavailability with great potential for the treatment of both pandemic and seasonal influenza.
ABSTRACT
A series of high affinity second-generation thiazolopiperidine inhibitors of PI3Kγ were designed based on some general observations around lipid kinase structure. Optimization of the alkylimidazole group led to inhibitors with higher levels of PI3Kγ selectivity. Additional insights into PI3K isoform selectivity related to sequence differences in a known distal hydrophobic pocket are also described.
Subject(s)
Drug Discovery , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Phosphoinositide-3 Kinase Inhibitors , Piperidines/chemistry , Piperidines/pharmacology , Cell Line , Enzyme Inhibitors/metabolism , Humans , Hydrophobic and Hydrophilic Interactions , Isoenzymes/antagonists & inhibitors , Isoenzymes/chemistry , Isoenzymes/metabolism , Models, Molecular , Phosphatidylinositol 3-Kinases/chemistry , Phosphatidylinositol 3-Kinases/metabolism , Piperidines/metabolism , Protein Conformation , Substrate SpecificityABSTRACT
In our effort to develop agents for the treatment of influenza, a phenotypic screening approach utilizing a cell protection assay identified a series of azaindole based inhibitors of the cap-snatching function of the PB2 subunit of the influenza A viral polymerase complex. Using a bDNA viral replication assay (Wagaman, P. C., Leong, M. A., and Simmen, K. A. Development of a novel influenza A antiviral assay. J. Virol. Methods 2002, 105, 105-114) in cells as a direct measure of antiviral activity, we discovered a set of cyclohexyl carboxylic acid analogues, highlighted by VX-787 (2). Compound 2 shows strong potency versus multiple influenza A strains, including pandemic 2009 H1N1 and avian H5N1 flu strains, and shows an efficacy profile in a mouse influenza model even when treatment was administered 48 h after infection. Compound 2 represents a first-in-class, orally bioavailable, novel compound that offers potential for the treatment of both pandemic and seasonal influenza and has a distinct advantage over the current standard of care treatments including potency, efficacy, and extended treatment window.