ABSTRACT
Novel bicyclic adenosine A(2A) antagonists with an aminoquinazoline moiety were designed and synthesized. The optimization of the initial lead compound based on in vitro and in vivo activity has led to the discovery of a potent and selective class of adenosine A(2A) antagonists. The structure-activity relationships of this novel series of bicyclic aminoquinazoline derivatives as adenosine A(2A) antagonists are described in detail.
Subject(s)
Adenosine A2 Receptor Antagonists/chemistry , Quinazolines/chemistry , Receptor, Adenosine A2A/chemistry , Adenosine A2 Receptor Antagonists/chemical synthesis , Adenosine A2 Receptor Antagonists/pharmacokinetics , Animals , Binding Sites , Drug Design , Half-Life , Humans , Inhibitory Concentration 50 , Molecular Docking Simulation , Protein Structure, Tertiary , Quinazolines/chemical synthesis , Quinazolines/pharmacokinetics , Rats , Receptor, Adenosine A2A/metabolism , Structure-Activity RelationshipABSTRACT
The optimization of oxazole-based PDE4 inhibitor 1 has led to the identification of both oral (compound 16) and inhaled (compound 34) PDE4 inhibitors. Selectivity against PDE10/PDE11, off target screening, and in vivo activity in the rat are discussed.
Subject(s)
Cyclic Nucleotide Phosphodiesterases, Type 4/chemistry , Oxazoles/chemistry , Proline/analogs & derivatives , Quinolines/chemical synthesis , Administration, Oral , Animals , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Drug Evaluation, Preclinical , Half-Life , Inhalation , Oxazoles/chemical synthesis , Oxazoles/pharmacokinetics , Phosphodiesterase 4 Inhibitors/chemical synthesis , Phosphodiesterase 4 Inhibitors/chemistry , Phosphodiesterase 4 Inhibitors/pharmacokinetics , Proline/chemical synthesis , Proline/chemistry , Proline/pharmacokinetics , Quinolines/chemistry , Quinolines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Optimization of oxazole-based PDE4 inhibitors has led to the discovery of a series of quinolyl oxazoles, with 4-benzylcarboxamide and 5-α-aminoethyl groups which exhibit picomolar potency against PDE4. Selectivity profiles and in vivo biological activity are also reported.
Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Cyclic Nucleotide Phosphodiesterases, Type 4/chemistry , Oxazoles/chemical synthesis , Phosphodiesterase 4 Inhibitors/chemical synthesis , Quinolines/chemical synthesis , Animals , Anti-Inflammatory Agents/pharmacology , Cyclic N-Oxides/chemistry , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Drug Discovery , Humans , Models, Molecular , Oxazoles/pharmacology , Phosphodiesterase 4 Inhibitors/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Rats , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/antagonists & inhibitorsABSTRACT
The structure-activity relationship studies of a novel sulfonylurea series of piperazine pyridazine-based small molecule glucan synthase inhibitors is described. The optimization of PK profiles within the series led to the discovery of several compounds with improved pharmacokinetic profiles which demonstrated in vitro potency against clinically relevant strains. However, the advancement of compounds from this series into a non-lethal systemic fungal infection model failed to show in vivo efficacy.
Subject(s)
Antifungal Agents/chemistry , Enzyme Inhibitors/chemistry , Glucosyltransferases/antagonists & inhibitors , Lead/chemistry , Piperazines/chemistry , Pyridazines/chemistry , Sulfonylurea Compounds/chemistry , Animals , Antifungal Agents/pharmacology , Candida/drug effects , Cell Line , Enzyme Inhibitors/pharmacology , Humans , Molecular Structure , Piperazine , Pyridazines/pharmacology , Rats , Structure-Activity Relationship , Sulfonylurea Compounds/pharmacologyABSTRACT
A detailed structure-activity relationship study of a novel series of pyridazine-based small molecule glucan synthase inhibitors is described. The optimization of the PK profile of this series led to the discovery of compound 11g, which demonstrated in vivo potency ip in a lethal fungal infection model.
Subject(s)
Antifungal Agents/chemistry , Enzyme Inhibitors/chemistry , Glucosyltransferases/antagonists & inhibitors , Pyridazines/chemistry , Sulfonamides/chemistry , Animals , Antifungal Agents/pharmacokinetics , Antifungal Agents/therapeutic use , Candida/drug effects , Candidiasis/drug therapy , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/therapeutic use , Glucosyltransferases/metabolism , Half-Life , Mice , Microbial Sensitivity Tests , Pyridazines/pharmacokinetics , Pyridazines/therapeutic use , Rats , Structure-Activity Relationship , Sulfonamides/pharmacokinetics , Sulfonamides/therapeutic useABSTRACT
The echinocandins are a class of semisynthetic natural products that target ß-1,3-glucan synthase (GS). Their proven clinical efficacy combined with minimal safety issues has made the echinocandins an important asset in the management of fungal infection in a variety of patient populations. However, the echinocandins are delivered only parenterally. A screen for antifungal bioactivities combined with mechanism-of-action studies identified a class of piperazinyl-pyridazinones that target GS. The compounds exhibited in vitro activity comparable, and in some cases superior, to that of the echinocandins. The compounds inhibit GS in vitro, and there was a strong correlation between enzyme inhibition and in vitro antifungal activity. In addition, like the echinocandins, the compounds caused a leakage of cytoplasmic contents from yeast and produced a morphological response in molds characteristic of GS inhibitors. Spontaneous mutants of Saccharomyces cerevisiae with reduced susceptibility to the piperazinyl-pyridazinones had substitutions in FKS1. The sites of these substitutions were distinct from those conferring resistance to echinocandins; likewise, echinocandin-resistant isolates remained susceptible to the test compounds. Finally, we present efficacy and pharmacokinetic data on an example of the piperazinyl-pyridazinone compounds that demonstrated efficacy in a murine model of Candida glabrata infection.
Subject(s)
Antifungal Agents/pharmacology , Glucosyltransferases/antagonists & inhibitors , Animals , Antifungal Agents/chemistry , Candida glabrata/drug effects , Candida glabrata/enzymology , Candida glabrata/pathogenicity , Candidiasis/drug therapy , Male , Mice , Molecular Structure , Piperazines/chemistry , Piperazines/pharmacology , Pyridazines/chemistry , Pyridazines/pharmacology , Saccharomyces cerevisiae/drug effects , Saccharomyces cerevisiae/enzymologyABSTRACT
A novel series of pyridazinone analogs has been developed as potent ß-1,3-glucan synthase inhibitors through structure-activity relationship study of the lead 5-[4-(benzylsulfonyl)piperazin-1-yl]-4-morpholino-2-phenyl-pyridazin-3(2H)-one (1). The effect of changes to the core structure is described in detail. Optimization of the sulfonamide moiety led to the identification of important compounds with much improved systematic exposure while retaining good antifungal activity against the fungal strains Candida glabrata and Candida albicans.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Glucosyltransferases/antagonists & inhibitors , Pyridazines/chemical synthesis , Pyridazines/pharmacology , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Candida albicans/drug effects , Candida glabrata/drug effects , Enzyme Inhibitors/chemistry , Molecular Structure , Pyridazines/chemistry , Structure-Activity RelationshipABSTRACT
A structure-activity relationship study of the lead 5-[4-(benzylsulfonyl)piperazin-1-yl]-4-morpholino-2-phenyl-pyridazin-3(2H)-one 1 has resulted in the identification of 2-(3,5-difluorophenyl)-4-(3-fluorocyclopentyloxy)-5-[4-(isopropylsulfonyl)piperazin-1-yl]-pyridazin-3(2H)-one 11c as a ß-1,3-glucan synthase inhibitor. Compound 11c exhibited significant efficacy in an in vivo mouse model of Candida glabrata infection.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Glucosyltransferases/antagonists & inhibitors , Pyridazines/chemistry , Pyridazines/pharmacology , Enzyme Inhibitors/chemical synthesis , Pyridazines/chemical synthesis , Structure-Activity RelationshipABSTRACT
A structurally-diverse series of carboxylate derivatives based on the 1,2,5-thiadiazolidin-one 1,1 dioxide scaffold were synthesized and used to probe the S' subsites of human neutrophil elastase (HNE) and neutrophil proteinase 3 (Pr 3). Several compounds are potent inhibitors of HNE but devoid of inhibitory activity toward Pr 3, suggesting that the S' subsites of HNE exhibit significant plasticity and can, unlike Pr 3, tolerate various large hydrophobic groups. The results provide a promising framework for the design of highly selective inhibitors of the two enzymes.
Subject(s)
Leukocyte Elastase/antagonists & inhibitors , Protease Inhibitors/chemistry , Cyclic S-Oxides/chemical synthesis , Cyclic S-Oxides/chemistry , Cyclic S-Oxides/pharmacology , Humans , Kinetics , Leukocyte Elastase/metabolism , Myeloblastin/antagonists & inhibitors , Myeloblastin/metabolism , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Thiazoles/chemical synthesis , Thiazoles/chemistry , Thiazoles/pharmacologyABSTRACT
Substituted quinolyl oxazoles were discovered as a novel and highly potent series of phosphodiesterase 4 (PDE4) inhibitors. Structure-activity relationship studies revealed that the oxazole core, with 4-carboxamide and 5-aminomethyl groups, is a novel PDE4 inhibitory pharmacophore. Selectivity profiles and in vivo biological activity are also reported.