RESUMO
A series of substituted oxindole derivatives was synthesized and evaluated for growth hormone (GH) releasing activity using cultured rat pituitary cells. (+)-6-Carbamoyl-3-(2-chlorophenyl)-(2-diethylaminoethyl)-4-trifluoromethyloxindole (SM-130686, 37S) was found to have potent activity (EC(50) = 3.0 nM), while the other enantiomer 37R had reduced activity. The absolute configuration of 37S was confirmed by X-ray crystallographic analysis. Compound 37S showed a good pharmacokinetic profile in rats with 28% oral bioavailability at 10 mg/kg and excellent in vivo activity as evidenced by a significant weight gain after 4 days of oral administration at 10 mg/kg twice a day. Compound 37S displaced the binding of (35)S-MK-677 to human GHS-R with an IC(50) value of 1.2 +/- 0.2 nM.
Assuntos
Etilaminas/síntese química , Hormônio do Crescimento/metabolismo , Indóis/síntese química , Receptores Acoplados a Proteínas G , Administração Oral , Animais , Disponibilidade Biológica , Peso Corporal/efeitos dos fármacos , Células CHO , Cricetinae , Cristalografia por Raios X , Etilaminas/química , Etilaminas/farmacologia , Feminino , Hormônio do Crescimento Humano/metabolismo , Humanos , Técnicas In Vitro , Indóis/química , Indóis/farmacologia , Masculino , Modelos Moleculares , Conformação Molecular , Adeno-Hipófise/citologia , Adeno-Hipófise/metabolismo , Ratos , Ratos Endogâmicos F344 , Ratos Wistar , Receptores de Superfície Celular/metabolismo , Receptores de Grelina , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Several O-acylated derivatives of bruceolide (2) were synthesized and their anti-malarial activities together with selective toxicities were examined. It was found that 3,15-di-O-acetyl-(3c), 3,15-di-O-propionyl-(3d) and 15-O-propionylbruceolide (3b), as well as bruceine B (3a), exhibited potent anti-malarial activities with high selective toxicities.