RESUMO
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.
Assuntos
Antifúngicos/síntese química , Candida/efeitos dos fármacos , Moduladores de Transporte de Membrana , Proteínas de Membrana Transportadoras/antagonistas & inibidores , Piperazinas/síntese química , Quinazolinas/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Candida/enzimologia , Candida albicans/efeitos dos fármacos , Candida albicans/enzimologia , Candida glabrata/efeitos dos fármacos , Candida glabrata/enzimologia , Farmacorresistência Fúngica , Sinergismo Farmacológico , Fluconazol/química , Fluconazol/farmacologia , Proteínas Fúngicas/antagonistas & inibidores , Humanos , Testes de Sensibilidade Microbiana , Piperazinas/química , Piperazinas/farmacologia , Quinazolinas/química , Quinazolinas/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Antidepressivos/farmacologia , Transtorno Depressivo/tratamento farmacológico , Inibidores de Fosfodiesterase/farmacologia , Antidepressivos/administração & dosagem , Antidepressivos/efeitos adversos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Relação Dose-Resposta a Droga , Humanos , Inibidores da Monoaminoxidase/farmacologia , Inibidores de Fosfodiesterase/administração & dosagem , Inibidores de Fosfodiesterase/efeitos adversos , Relação Estrutura-Atividade , Vômito/induzido quimicamenteRESUMO
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.
Assuntos
Antibacterianos/farmacologia , Proteínas da Membrana Bacteriana Externa/metabolismo , Transporte Biológico Ativo/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/metabolismo , Animais , Antibacterianos/metabolismo , Resistência Microbiana a Medicamentos , Regulação Bacteriana da Expressão Gênica , Lactamas/metabolismo , Camundongos , Testes de Sensibilidade Microbiana , Neutropenia/tratamento farmacológico , Ligação Proteica , Sepse/tratamento farmacológico , Albumina Sérica/metabolismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antibacterianos/farmacologia , Proteínas da Membrana Bacteriana Externa/metabolismo , Transporte Biológico Ativo/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/metabolismo , Animais , Antibacterianos/metabolismo , Resistência Microbiana a Medicamentos , Fluoroquinolonas/farmacologia , Regulação Bacteriana da Expressão Gênica , Lactamas/metabolismo , Levofloxacino , Camundongos , Testes de Sensibilidade Microbiana , Neutropenia/tratamento farmacológico , Ofloxacino/farmacologia , Ligação Proteica , Ratos , Sepse/tratamento farmacológico , Albumina Sérica/metabolismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Anti-Infecciosos/farmacocinética , Transporte Biológico Ativo/efeitos dos fármacos , Diaminas/farmacocinética , Plasma/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacos , Animais , Anti-Infecciosos/administração & dosagem , Anti-Infecciosos/farmacologia , Proteínas da Membrana Bacteriana Externa/metabolismo , Diaminas/administração & dosagem , Diaminas/farmacologia , Infusões Intravenosas , Metabolismo dos Lipídeos , Masculino , Testes de Sensibilidade Microbiana , Ofloxacino/metabolismo , Ofloxacino/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
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.
Assuntos
Aminoquinolinas/síntese química , Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Proteínas da Membrana Bacteriana Externa/antagonistas & inibidores , Levofloxacino , Moduladores de Transporte de Membrana , Proteínas de Membrana Transportadoras/antagonistas & inibidores , Ofloxacino/farmacologia , Aminobutiratos/química , Aminoquinolinas/farmacologia , Aminoquinolinas/toxicidade , Animais , Anti-Infecciosos/toxicidade , Sinergismo Farmacológico , Dose Letal Mediana , Camundongos , Ornitina/química , Pseudomonas aeruginosa/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antifúngicos/farmacologia , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/genética , Tubulina (Proteína)/genética , Antifúngicos/química , Benzimidazóis/química , Benzimidazóis/farmacologia , Sítios de Ligação , Desenho de Fármacos , Testes de Sensibilidade Microbiana , Mutação , PolímerosRESUMO
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.