RESUMO
Cyclic nucleotide cAMP is a ubiquitous secondary messenger involved in a plethora of cellular responses to biological agents involving activation of adenylyl cyclase. Its intracellular levels are tightly controlled by a family of cyclic nucleotide degrading enzymes, the PDEs. In recent years, cyclic nucleotide phosphodiesterase type 4 (PDE4) has aroused scientific attention as a suitable target for anti-inflammatory therapy in respiratory diseases, particularly in the management of asthma and COPD. Here we describe our efforts to discover novel, highly potent inhaled inhibitors of PDE4. Through structure based design, with the inclusion of a variety of functional groups and physicochemical profiles in order to occupy the solvent-filled pocket of the PDE4 enzyme, we modified the structure of our oral PDE4 inhibitors to reach compounds down to picomolar enzymatic potencies while at the same time tackling successfully an uncovered selectivity issue with the adenosine receptors. In vitro potencies were demonstrated in a rat lung neutrophilia model by administration of a suspension with a Penn-Century MicroSprayer Aerosolizer.
Assuntos
Compostos de Bifenilo/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Inibidores da Fosfodiesterase 4/farmacologia , Piridazinas/farmacologia , Animais , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/química , Relação Dose-Resposta a Droga , Humanos , Masculino , Modelos Moleculares , Estrutura Molecular , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/química , Piridazinas/síntese química , Piridazinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
A series of pyrido[3',2':4,5]furo[3,2-d]pyrimidines (PFP) were synthesized and tested for phosphodiesterase type 4 (PDE4) inhibitory activity, with the potential to treat asthma and chronic obstructive pulmonary disease (COPD). Structure-activity relationships within this series, leading to an increase of potency on the enzyme, is presented. Both gem-dimethylcyclohexyl moieties fused to the pyridine ring and the substitution at the 5 position of the PFP scaffold, proved to be key elements in order to get a high affinity in the enzyme.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Animais , Asma/tratamento farmacológico , Asma/enzimologia , Células CACO-2 , Permeabilidade da Membrana Celular , Furões , Humanos , Modelos Moleculares , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/farmacocinética , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/enzimologia , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Relação Estrutura-AtividadeRESUMO
A series of pyrido[3',2':4,5]thieno[3,2-d]pyrimidines (PTP) has been synthesized and tested as phosphodiesterase IV inhibitors (PDE4), a target for the treatment of asthma and chronic obstructive pulmonary disease (COPD). Structure-activity relationships within this series, leading to an increase of potency on the enzyme, are presented. The gem-dimethylcycloalkyl moiety fused to the pyridine ring proved to be a key element of the scaffold in order to get a higher affinity in the enzyme.
Assuntos
Inibidores da Fosfodiesterase 4 , Piridinas/síntese química , Pirimidinas/síntese química , Tiofenos/síntese química , Humanos , Pichia , Piridinas/química , Pirimidinas/química , Proteínas Recombinantes/antagonistas & inibidores , Relação Estrutura-Atividade , Tiofenos/químicaRESUMO
The frequency of hepatic hydrothorax in cirrhotic patients is reported to be approximately 5%. The pleural effusion is predominantly right-sided (85% of cases) but may be bilateral. Although most often accompanied by significant ascites, it can occur in its absence. We report a case of a right-sided acute hepatic hydrothorax as a result of residual motor blockade during anesthesia recovery and without previous evidence of clinical ascites. This complication should be considered by the anesthesiologist in every cirrhotic patient, with or without clinical evidence of ascites.