RESUMO
The orexin/hypocretin receptors are a family of G protein-coupled receptors and consist of orexin-1 (OX1) and orexin-2 (OX2) receptor subtypes. Orexin receptors are expressed throughout the central nervous system and are involved in the regulation of the sleep/wake cycle. Because modulation of these receptors constitutes a promising target for novel treatments of disorders associated with the control of sleep and wakefulness, such as insomnia, the development of orexin receptor antagonists has emerged as an important focus in drug discovery research. Here, we report the design, synthesis, characterization, and structure-activity relationships (SARs) of novel orexin receptor antagonists. Various modifications made to the core structure of a previously developed compound (-)-5, the lead molecule, resulted in compounds with improved chemical and pharmacological profiles. The investigation afforded a potential therapeutic agent, (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide (E2006), an orally active, potent orexin antagonist. The efficacy was demonstrated in mice in an in vivo study by using sleep parameter measurements.
Assuntos
Amidas/química , Aminopiridinas/farmacologia , Ciclopropanos/química , Desenho de Fármacos , Descoberta de Drogas , Antagonistas dos Receptores de Orexina , Pirimidinas/farmacologia , Administração Oral , Aminopiridinas/administração & dosagem , Animais , Cálcio/metabolismo , Células Cultivadas , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Receptores de Orexina/metabolismo , Pirimidinas/administração & dosagem , Relação Estrutura-AtividadeRESUMO
We present efficient syntheses of serofendic acids A and B (SA-A and SA-B), novel neuroprotective substances isolated from fetal calf serum. Biological and pharmacological evaluation showed that SA-A and SA-B have potent protective action against glutamate-induced neurotoxicity, but do not interact directly with glutamate receptors. A pharmacokinetic study showed that they have good oral bioavailability in rats. The results indicate that SA-A and SA-B are potential lead compounds for candidate drugs to treat various neurological disorders.
Assuntos
Diterpenos/síntese química , Diterpenos/farmacologia , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/farmacologia , Administração Oral , Animais , Bovinos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Córtex Cerebral/citologia , Cristalografia por Raios X , Diterpenos/administração & dosagem , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Sangue Fetal/química , Ácido Glutâmico/toxicidade , Injeções Intravenosas , Modelos Moleculares , Conformação Molecular , Neurônios/citologia , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
Analogues of serofendic acid were prepared and their protective effects against L-glutamate (Glu)-induced neurotoxicity were examined using primary cultures of rat cortical neurons. Some analogues exhibited similar neuroprotective activity to that of serofendic acid.