RESUMO
Brain protection of the newborn remains a challenging priority and represents a totally unmet medical need. Pharmacological inhibition of caspases appears as a promising strategy for neuroprotection. In a translational perspective, we have developed a pentapeptide-based group II caspase inhibitor, TRP601/ORPHA133563, which reaches the brain, and inhibits caspases activation, mitochondrial release of cytochrome c, and apoptosis in vivo. Single administration of TRP601 protects newborn rodent brain against excitotoxicity, hypoxia-ischemia, and perinatal arterial stroke with a 6-h therapeutic time window, and has no adverse effects on physiological parameters. Safety pharmacology investigations, and toxicology studies in rodent and canine neonates, suggest that TRP601 is a lead compound for further drug development to treat ischemic brain damage in human newborns.
Assuntos
Inibidores de Caspase , Inibidores de Cisteína Proteinase/uso terapêutico , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Isquemia/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Oligopeptídeos/uso terapêutico , Quinolinas/farmacologia , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Sítios de Ligação , Caspases/metabolismo , Inibidores de Cisteína Proteinase/química , Citocromos c/metabolismo , Modelos Animais de Doenças , Hipóxia-Isquemia Encefálica/patologia , Isquemia/patologia , Camundongos , Fármacos Neuroprotetores/química , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Quinolinas/química , RatosAssuntos
Inibidores de Caspase , Inibidores Enzimáticos/farmacologia , Clorometilcetonas de Aminoácidos/farmacologia , Animais , Compostos de Benzil/farmacologia , Catepsinas/antagonistas & inibidores , Humanos , Hidrocarbonetos Fluorados/farmacologia , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Quinolinas/farmacologiaRESUMO
The direct and indirect stereochemical resolution of the enantiomers of ring- and alpha-methyl-substituted phenylalanines and phenylalanine amides was attempted by high-performance liquid chromatographic methods. The direct separation was carried out on two chiral stationary phases, the crown-ether-based Crownpak CR(+), and the teicoplanin-based Chirobiotic T, while the indirect resolution was performed by applying pre-column derivatization with 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl isothiocyanate (GITC) and Nalpha-(2,4-dinitro-5-fluorophenyl)-L-alanine amide (Marfey's reagent, FDAA). The Chirobiotic T column was efficient in the separation of ring- and alpha-methyl-substituted phenylalanine analogues, but was ineffective for the amides of these analogues. The Crownpak CR(+) column separated the ring-substituted phenylalanines and amides, whereas the alpha-methylated analogues were coeluted. Of the two indirect methods, GITC derivatization seemed more effective than FDAA derivatization.
