RESUMO
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.
Assuntos
Descoberta de Drogas , Fenol/síntese química , Ureia/síntese química , Agonistas de Receptores Adrenérgicos beta 2 , Estrutura Molecular , Fenol/química , Fenol/farmacologia , Relação Quantitativa Estrutura-Atividade , Ureia/química , Ureia/farmacologiaRESUMO
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.
Assuntos
Carbolinas/química , Química Farmacêutica/métodos , Antagonistas de Leucotrienos/síntese química , Receptores de Leucotrienos/química , Administração Oral , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Desenho de Fármacos , Cobaias , Humanos , Concentração Inibidora 50 , Antagonistas de Leucotrienos/farmacologia , Modelos Químicos , Relação Estrutura-Atividade , Fatores de TempoRESUMO
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.
Assuntos
Antagonistas dos Receptores Histamínicos H1/síntese química , Piridinas/síntese química , Administração Oral , Animais , Barreira Hematoencefálica , Permeabilidade Capilar , Cobaias , Antagonistas dos Receptores Histamínicos H1/farmacocinética , Antagonistas dos Receptores Histamínicos H1/farmacologia , Humanos , Concentração Inibidora 50 , Piridinas/farmacocinética , Piridinas/farmacologia , Ratos , Solubilidade , Relação Estrutura-AtividadeRESUMO
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.