ABSTRACT
Hematopoietic prostaglandin D synthase (HPGDS) is primarly expressed in mast cells, antigen-presenting cells, and Th-2 cells. HPGDS converts PGH2 into PGD2, a mediator thought to play a pivotal role in airway allergy and inflammatory processes. In this letter, we report the discovery of an orally potent and selective inhibitor of HPGDS that reduces the antigen-induced response in allergic sheep.
ABSTRACT
The discovery and initial optimization of a novel anthranilic acid derived class of antibacterial agents has been described in a recent series of papers. This paper describes the discovery of 1-acylindazol-3-ols as a novel bioisostere of an anthranilic acid. The synthesis and structure-activity relationships of the indazol bioisosteres are described herein.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Indazoles/chemical synthesis , Indazoles/pharmacology , Protein Biosynthesis/drug effects , Staphylococcus aureus/drug effects , ortho-Aminobenzoates/chemistry , Anti-Bacterial Agents/chemistry , Combinatorial Chemistry Techniques , Crystallography, X-Ray , Indazoles/chemistry , Microbial Sensitivity Tests , Molecular Conformation , Molecular Structure , Structure-Activity RelationshipABSTRACT
We report a new class of non-nucleoside antivirals, the 7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamides, some of which possess remarkable potency versus a broad spectrum of herpesvirus DNA polymerases and excellent selectivity compared to human DNA polymerases. A critical factor in the level of activity is hypothesized to be conformational restriction of the key 2-aryl-2-hydroxyethylamine sidechain by an adjacent methyl group.
Subject(s)
Cytomegalovirus/enzymology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Nucleic Acid Synthesis Inhibitors , Pyridines/chemistry , Pyridines/chemical synthesis , Pyridines/pharmacology , Structure-Activity RelationshipABSTRACT
In the past few years, a significant effort has been devoted by Pharmacia toward the discovery of novel antibiotics. We have recently described the identification of an anthranilic acid lead 1 and the optimization resulting in the advanced lead 2. In this report, we describe the preparation of several selected amide bioisosteres connecting the A- and the B-rings. The E-alkene provided a rigid analog with equal potency to the corresponding amide. This indicates that the amide is not a recognition element rather acts as an appropriate spatial linker of the two important aryl A and B rings. The work here clearly demonstrates that the amide linker can be replaced with several functionalities without significant deterioration in the MIC activity.
Subject(s)
Anti-Bacterial Agents/pharmacology , ortho-Aminobenzoates/chemistry , ortho-Aminobenzoates/pharmacology , Anti-Bacterial Agents/chemistry , Drug Design , Drug Resistance, Bacterial , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity RelationshipABSTRACT
Discovery of novel antibacterial agents is a significant challenge. We have recently reported on our discovery of novel antibacterial agents in which we have rapidly optimized potency utilizing a parallel chemistry approach. These advanced leads suffer from high affinity for human serum albumin (HSA). In an effort to decrease the affinity for HSA we have prepared a series of heterocyclic analogs, which retained antibacterial activity and demonstrated reduced affinity for HSA.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacokinetics , Bacteria/drug effects , Heterocyclic Compounds , Humans , Microbial Sensitivity Tests , Protein Binding , Serum Albumin/metabolism , Structure-Activity Relationship , ortho-AminobenzoatesABSTRACT
There have recently been developments in the methods used to access the accuracy of the prediction and applicability domain of absorption, distribution, metabolism, excretion and toxicity models, and also in the methods used to predict the physicochemical properties of compounds in the early stages of drug development. The methods are classified into two main groups: those based on the analysis of similarity of molecules, and those based on the analysis of calculated properties. An analysis of octanol-water distribution coefficients is used to exemplify the consistency of estimated and calculated accuracy of the ALOGPS program (http://www.vcclab.org) to predict in-house and publicly available datasets.
Subject(s)
Drug Design , Pharmaceutical Preparations/chemistry , Algorithms , Animals , Computer Simulation , Drug-Related Side Effects and Adverse Reactions , Humans , Inactivation, Metabolic , Models, Biological , Pharmaceutical Preparations/metabolism , Reproducibility of ResultsABSTRACT
Six docking programs (FlexX, GOLD, ICM, LigandFit, the Northwestern University version of DOCK, and QXP) were evaluated in terms of their ability to reproduce experimentally observed binding modes (poses) of small-molecule ligands to macromolecular targets. The accuracy of a pose was assessed in two ways: First, the RMS deviation of the predicted pose from the crystal structure was calculated. Second, the predicted pose was compared to the experimentally observed one regarding the presence of key interactions with the protein. The latter assessment is referred to as interactions-based accuracy classification (IBAC). In a number of cases significant discrepancies were found between IBAC and RMSD-based classifications. Despite being more subjective, the IBAC proved to be a more meaningful measure of docking accuracy in all these cases.