RESUMO
The role of immunologically released mediators, such as histamine, leukotrienes, and platelet-activating factor, is well-established for asthma and other allergic disorders. Developing therapeutic agents which would block mediator release from mast cells and other relevant cell types would provide a rational approach to asthma therapy. Using human basophil as a screen, a series of 4-aryl-2-(phenylamino)pyrimidines was found which inhibited mediator release. These compounds were prepared by condensing acetyl heterocycles with dimethylformamide dimethyl acetal to form enaminones which are cyclized with aryl guanidines to give pyrimidines. After examining a large number of analogs, N-[3-(1H-imidazol-1-yl)phenyl]-4-(2-pyridinyl)-2- pyrimidinamine (1-27) was chosen for toxicological evaluation.
Assuntos
Antagonistas dos Receptores Histamínicos/síntese química , Imidazóis/síntese química , Pirimidinas/síntese química , Animais , Basófilos/efeitos dos fármacos , Basófilos/metabolismo , Feminino , Humanos , Imidazóis/química , Imidazóis/farmacologia , Dose Letal Mediana , Macaca mulatta , Masculino , Camundongos , Anafilaxia Cutânea Passiva/efeitos dos fármacos , Pirimidinas/química , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
The synthesis of the title compounds has been accomplished. The N-iminoacetic acid analogues (12a and 12b) containing the aminothiazole type side chain exhibited good in vitro antibacterial activity against Gram-negative organisms. The corresponding N-glycyl derivative (17) was not active.
Assuntos
Antibacterianos/síntese química , Compostos Aza/síntese química , Monobactamas/síntese química , Antibacterianos/farmacologia , Compostos Aza/farmacologia , Fenômenos Químicos , Química , Bactérias Gram-Negativas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Monobactamas/farmacologiaRESUMO
By using inhibition of histamine release from antigen-challenged, sensitized human basophils as a means of identifying a potentially prophylactic drug for the treatment of asthma, a series of substituted imidazo[1,5-d][1,2,4]triazines were found, which were active. These compounds were prepared by treating imidazolecarboxaldehydes with excess Grignard agent and then oxidizing the resulting alcohols to ketones with Jones reagent. Pyrolysis of a mixture of ketone and methyl carbazate at 200 degrees C in diphenyl ether produced the desired imidazo[1,5-d][1,2,4]triazines. Those compounds with the greatest basophil activity were tested for in vivo activity in the mouse passive cutaneous anaphylaxis (PCA) and the guinea pig passive anaphylaxis tests. The best compounds, 1-ethyl-8-methyl-6-propylimidazo[1,5-d][1,2,4]triazin-4(3H)- one (4-17) and 1,8-dimethyl-6-propylimidazo[1,5-d][1,2,4]triazin-4-(3H)-one (4-16) were chosen for further study.
