ABSTRACT
Structure-activity relationships of a novel series of fungal efflux pump inhibitors with respect to potentiation of the activity of fluconazole against strains of Candida albicans and Candida glabrata over-expressing ABC-type efflux pumps are systematically explored.
Subject(s)
Antifungal Agents/chemical synthesis , Candida/drug effects , Membrane Transport Modulators , Membrane Transport Proteins/antagonists & inhibitors , Piperazines/chemical synthesis , Quinazolines/chemical synthesis , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Candida/enzymology , Candida albicans/drug effects , Candida albicans/enzymology , Candida glabrata/drug effects , Candida glabrata/enzymology , Drug Resistance, Fungal , Drug Synergism , Fluconazole/chemistry , Fluconazole/pharmacology , Fungal Proteins/antagonists & inhibitors , Humans , Microbial Sensitivity Tests , Piperazines/chemistry , Piperazines/pharmacology , Quinazolines/chemistry , Quinazolines/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The potential use of phosphodiesterase 4 (PDE4) inhibitors to treat various inflammatory diseases such as asthma and chronic obstructive pulmonary disease has garnered significant attention from the pharmaceutical industry over the last few years. In contrast, the potential use of PDE4 inhibitors to treat central nervous system disorders, such as major depressive disorders, has received less attention. With a growing body of work linking intracellular signaling pathways such as modulation of the cAMP second messenger system to a positive outcome following antidepressant therapy, the role that PDE4 inhibitors could play in the treatment of mood disorders has become more apparent. The following review examines the promise that PDE4 inhibitors may hold for the treatment of these diseases.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Antidepressive Agents/pharmacology , Depressive Disorder/drug therapy , Phosphodiesterase Inhibitors/pharmacology , Antidepressive Agents/administration & dosage , Antidepressive Agents/adverse effects , Cyclic Nucleotide Phosphodiesterases, Type 4 , Dose-Response Relationship, Drug , Humans , Monoamine Oxidase Inhibitors/pharmacology , Phosphodiesterase Inhibitors/administration & dosage , Phosphodiesterase Inhibitors/adverse effects , Structure-Activity Relationship , Vomiting/chemically inducedABSTRACT
The identification of a series of compounds that specifically inhibit efflux by the MexAB-OprM pump system in Pseudomonas aeruginosa is described. Synthesis and in vitro structure-activity relationships (SARs) are outlined. Early leads lacked activity in animal models, and efforts to improve solubility and reduce serum protein binding by the introduction of polar groups are discussed.
Subject(s)
Anti-Bacterial Agents/pharmacology , Bacterial Outer Membrane Proteins/metabolism , Biological Transport, Active/drug effects , Carrier Proteins/metabolism , Membrane Transport Proteins/metabolism , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/metabolism , Animals , Anti-Bacterial Agents/metabolism , Drug Resistance, Microbial , Gene Expression Regulation, Bacterial , Lactams/metabolism , Mice , Microbial Sensitivity Tests , Neutropenia/drug therapy , Protein Binding , Sepsis/drug therapy , Serum Albumin/metabolism , Structure-Activity RelationshipABSTRACT
Problems of low solubility, high serum protein binding, and lack of efficacy in vivo in first generation MexAB-OprM specific efflux pump inhibitors were addressed. Through the use of pharmacophore modelling, the key structural elements for pump inhibition were defined. Use of alternative scaffolds upon which the key elements were arrayed gave second generation leads with greatly improved physical properties and activity in the potentiation of antibacterial quinolones (levofloxacin and sitafloxacin) versus Pseudomonas aeruginosa in vivo.
Subject(s)
Anti-Bacterial Agents/pharmacology , Bacterial Outer Membrane Proteins/metabolism , Biological Transport, Active/drug effects , Carrier Proteins/metabolism , Membrane Transport Proteins/metabolism , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/metabolism , Animals , Anti-Bacterial Agents/metabolism , Drug Resistance, Microbial , Fluoroquinolones/pharmacology , Gene Expression Regulation, Bacterial , Lactams/metabolism , Levofloxacin , Mice , Microbial Sensitivity Tests , Neutropenia/drug therapy , Ofloxacin/pharmacology , Protein Binding , Rats , Sepsis/drug therapy , Serum Albumin/metabolism , Structure-Activity RelationshipABSTRACT
Following the optimization of diamine-containing efflux pump inhibitors with respect to in vitro potentiation activity, in vivo stability and acute toxicity, we addressed the question of how to control the pharmacokinetic properties of the series. Upon intravenous administration in the rat, tissue levels of MC-04,124 (the lead compound) were high and prolonged compared to those in the serum. The lipophilicity and basicity of analogues of this compound were systematically varied, and effects on potency and pharmacokinetics explored. The ratio of drug levels in tissue versus serum was not significantly reduced in any of the active analogues examined.
Subject(s)
Anti-Infective Agents/pharmacokinetics , Biological Transport, Active/drug effects , Diamines/pharmacokinetics , Plasma/drug effects , Pseudomonas aeruginosa/drug effects , Animals , Anti-Infective Agents/administration & dosage , Anti-Infective Agents/pharmacology , Bacterial Outer Membrane Proteins/metabolism , Diamines/administration & dosage , Diamines/pharmacology , Infusions, Intravenous , Lipid Metabolism , Male , Microbial Sensitivity Tests , Ofloxacin/metabolism , Ofloxacin/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Tissue DistributionABSTRACT
Conformational restriction of the ornithine residue of the efflux pump inhibitor D-ornithine-D-homophenylalanine-3-aminoquinoline (MC-02,595, 2) furnished bioisosteric proline derivatives that were less toxic in vivo and as active as the lead in potentiating the activity of the fluoroquinolone levofloxacin via the inhibition of efflux pumps in Pseudomonas aeruginosa.
Subject(s)
Aminoquinolines/chemical synthesis , Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/pharmacology , Bacterial Outer Membrane Proteins/antagonists & inhibitors , Levofloxacin , Membrane Transport Modulators , Membrane Transport Proteins/antagonists & inhibitors , Ofloxacin/pharmacology , Aminobutyrates/chemistry , Aminoquinolines/pharmacology , Aminoquinolines/toxicity , Animals , Anti-Infective Agents/toxicity , Drug Synergism , Lethal Dose 50 , Mice , Ornithine/chemistry , Pseudomonas aeruginosa/drug effects , Structure-Activity RelationshipABSTRACT
Compounds that selectively disrupt fungal mitosis have proven to be effective in controlling agricultural pests, but no specific mitotic inhibitor is available for the treatment of systemic mycoses in mammalian hosts. In an effort to identify novel mitotic inhibitors, we used a cell-based screening strategy that exploited the hypersensitivity of a yeast alpha-tubulin mutant strain to growth inhibition by antimitotic agents. The compounds identified inhibited yeast nuclear division and included one structural class of compounds shown to be fungus specific. MC-305904 and structural analogs inhibited fungal cell mitosis and inhibited the in vitro polymerization of fungal tubulin but did not block mammalian cell microtubule function or mammalian tubulin polymerization. Extensive analysis of yeast mutations that specifically alter sensitivity to MC-305904 structural analogs suggested that compounds in the series bind to a site on fungal beta-tubulin near amino acid 198. Features of the proposed binding site explain the observed fungal tubulin specificity of the series and are consistent with structure-activity relationships among a library of related compounds.
Subject(s)
Antifungal Agents/pharmacology , Saccharomyces cerevisiae/drug effects , Saccharomyces cerevisiae/genetics , Tubulin/genetics , Antifungal Agents/chemistry , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Binding Sites , Drug Design , Microbial Sensitivity Tests , Mutation , PolymersABSTRACT
Several classes of peptidomimetics of the efflux pump inhibitor D-ornithine-D-homophenylalanine-3-aminoquinoline (MC-02,595) have been prepared and evaluated for their ability to potentiate the activity of the fluoroquinolone levofloxacin in Pseudomonas aeruginosa. A number of the new analogues were as active or more active than the lead, demonstrating that a peptide backbone is not essential for activity.