RESUMO
Mechanistic information and structure-based design methods have been used to design a series of nonpeptide cyclic ureas that are potent inhibitors of human immunodeficiency virus (HIV) protease and HIV replication. A fundamental feature of these inhibitors is the cyclic urea carbonyl oxygen that mimics the hydrogen-bonding features of a key structural water molecule. The success of the design in both displacing and mimicking the structural water molecule was confirmed by x-ray crystallographic studies. Highly selective, preorganized inhibitors with relatively low molecular weight and high oral bioavailability were synthesized.
Assuntos
Azepinas/química , Desenho de Fármacos , Inibidores da Protease de HIV/química , Administração Oral , Animais , Azepinas/metabolismo , Azepinas/farmacocinética , Azepinas/farmacologia , Sítios de Ligação , Disponibilidade Biológica , Linhagem Celular , Cristalografia por Raios X , Cães , Avaliação Pré-Clínica de Medicamentos , Protease de HIV/química , Protease de HIV/metabolismo , Inibidores da Protease de HIV/metabolismo , Inibidores da Protease de HIV/farmacocinética , Inibidores da Protease de HIV/farmacologia , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Ligação de Hidrogênio , Modelos Moleculares , Conformação Molecular , Peso Molecular , Ratos , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Ureia , Replicação Viral/efeitos dos fármacosRESUMO
Repeated (once a day for 8 days) but not single administration of estradiol benzoate (10 micrograms/kg, s.c.) induced a sevenfold increase in anterior pituitary gamma-aminobutyric acid (GABA) concentration in male rats. GABA concentration also increased in the median eminence whereas no changes or decreases were observed in other brain regions including hypothalamic arcuate nucleus, lateral septum, hippocampus, caudate nucleus, and substantia nigra. Eight-day estradiol benzoate injection also enhanced the Vmax of median eminence glutamate decarboxylase activity without affecting the Km of the enzyme for glutamic acid. Taken together, these results suggest that repeated administration of estradiol benzoate increases the activity of the tubero-infundibular GABAergic system in male rats.