RESUMEN
The synthesis of diverse functionalized ureas in a semi-parallel fashion is described, as well as their ß(1)/ß(2)-adrenergic activities and the corresponding structure-activity relationship (SAR). We have focused on lipophilicity and duration of action, and we have discovered a strong correlation in this series of molecules. A quantitative structure-activity relationship (QSAR) analysis will be presented that quantifies this relationship.
Asunto(s)
Descubrimiento de Drogas , Fenol/síntesis química , Urea/síntesis química , Agonistas de Receptores Adrenérgicos beta 2 , Estructura Molecular , Fenol/química , Fenol/farmacología , Relación Estructura-Actividad Cuantitativa , Urea/química , Urea/farmacologíaRESUMEN
A gamma-carboline series of cysLT(1) receptor antagonists has been prepared. Some of the compounds show good potencies both, in vitro and in vivo, compared to the standard compounds.
Asunto(s)
Carbolinas/química , Química Farmacéutica/métodos , Antagonistas de Leucotrieno/síntesis química , Receptores de Leucotrienos/química , Administración Oral , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacología , Diseño de Fármacos , Cobayas , Humanos , Concentración 50 Inhibidora , Antagonistas de Leucotrieno/farmacología , Modelos Químicos , Relación Estructura-Actividad , Factores de TiempoRESUMEN
The synthesis and structure-activity relationships of piperidinylpyrrolopyridines as potent and selective H(1) antagonists are discussed. It was found that the nature of the acid chain bonded to piperidine was a key feature for maintaining both the duration of action in vivo and lack of sedative properties.
Asunto(s)
Antagonistas de los Receptores Histamínicos H1/síntesis química , Piridinas/síntesis química , Administración Oral , Animales , Barrera Hematoencefálica , Permeabilidad Capilar , Cobayas , Antagonistas de los Receptores Histamínicos H1/farmacocinética , Antagonistas de los Receptores Histamínicos H1/farmacología , Humanos , Concentración 50 Inhibidora , Piridinas/farmacocinética , Piridinas/farmacología , Ratas , Solubilidad , Relación Estructura-ActividadRESUMEN
A series of indolylpiperidinyl derivatives were prepared and evaluated for their activity as histamine H(1) antagonists. Structure-activity relationship studies were directed toward improving in vivo activity and pharmacokinetic profile of our first lead (1). Substitution of fluorine in position 6 on the indolyl ring led to higher in vivo activity in the inhibition of histamine-induced cutaneous vascular permeability assay but lower selectivity toward 5HT(2) receptor. Extensive optimization was carried out within this series and a number of histamine H(1) antagonists showing potency and long duration of action in vivo and low brain penetration or cardiotoxic potential were identified. Within this novel series, indolylpiperidines 15, 20, 48,51 and 52 exhibited a long half-life in rat and have been selected for further preclinical evaluation.
