RESUMEN
A new primate model has been developed for the evaluation of antiallergic agents. Compounds are tested for their ability to inhibit anti-IgE induced histamine release from the bronchoalveolar mast cells lavaged from the lungs of Macaca arctoides infected with the parasite Ascaris suum. A number of 6-substituted pyranoquinoline derivatives have been evaluated and the activities were subjected to Hansch analysis. A highly significant correlation with lipophilicity (pi) and Hammett sigma p values was obtained. The relationship was used to predict further compounds for synthesis giving rise to new, potent analogues. Some apparently anomalous results could be explained by differences in the ionization of, or tautomerism in, the quinoline ring.
Asunto(s)
Modelos Animales de Enfermedad , Hipersensibilidad/tratamiento farmacológico , Piranos/uso terapéutico , Quinolinas/uso terapéutico , Animales , Ascariasis/inmunología , Líquido del Lavado Bronquioalveolar/citología , Fenómenos Químicos , Química , Cromolin Sódico/uso terapéutico , Liberación de Histamina/efectos de los fármacos , Hipersensibilidad/inmunología , Inmunoglobulina E/inmunología , Macaca , Mastocitos/fisiología , Piranos/síntesis química , Piranos/farmacología , Quinolinas/síntesis química , Quinolinas/farmacología , Relación Estructura-ActividadRESUMEN
A number of antiallergic pyranquinolinedicarboxylic acid derivatives with potential for the topical treatment of asthma have been synthesized. All the compounds have been evaluated against rat passive cutaneous anaphylaxis and in a dog hypotension screen. This is the first detailed description of the application of the latter screen for the identification of antiallergic agents. Two compounds, disodium 9-ethyl-6, 9-dihydro-4,6-dioxo-10-propyl-4H-pyrano [3,2-g]quinoline-2,8-dicarboxylate (86) and disodium 6-(methylamino)-4-oxo-10-propyl-4H-pyrano[3,2-g]-quinoline-2, 8-dicarboxylate (72), were selected and further evaluated for their ability to induce phosphorylation of a 78000 molecular weight protein associated with the rat peritoneal mast cell. Their ability to inhibit histamine release from these cells and from a mucosal mast cell preparation has also been evaluated. These compounds, nedocromil sodium (TILADE 86) and minocromil (the free acid of 72), are at present undergoing therapeutic evaluation. The rationale for the screening procedure and the relevance of the second carboxylic acid function of these dibasic acids to receptor binding are discussed.