RESUMO
The influx of leukocytes (eosinophils, lymphocytes, and monocytes) into the airways and their production of proinflammatory cytokines contribute to the severity of allergic asthma. We describe here the synthesis and pharmacological evaluation of a series of triazinylphenylalkylthiazolecarboxylic acid esters that were designed to act as lung-specific antedrugs and inhibitors of the production of interleukin (IL)-5, a primary eosinophil-activating and proinflammatory cytokine. Closer examination of the hydroxypropyl ester, 15, indicated its high metabolic stability (t(1/2) > 240 min) in human lung S9 fraction but rapid conversion (t(1/2) = 15 min) into the pharmacologically inactive carboxylic acid by human liver preparations. In stimulated human whole blood cultures, 15 reduced not only the production of IL-5 (IC(50) = 78 nM) but also the biosynthesis of the monocyte chemotactic proteins MCP-1 (IC(50) = 220 nM), MCP-2 (IC(50) = 580 nM), and MCP-3 (IC(50) = 80 nM). In vivo, intratracheal administration of 15 (6 mg/animal) to allergic sheep, either before (-4 h) or after (+1.5 h) the pulmonary allergen challenge, completely abrogated the late-phase airway response and reduced the bronchial hyperreactivity to inhaled carbachol.
Assuntos
Asma/tratamento farmacológico , Broncodilatadores/síntese química , Citocinas/antagonistas & inibidores , Tiazóis/síntese química , Triazinas/síntese química , Adulto , Animais , Asma/imunologia , Asma/fisiopatologia , Broncodilatadores/metabolismo , Broncodilatadores/farmacologia , Quimiocina CCL2/antagonistas & inibidores , Quimiocina CCL2/biossíntese , Quimiocina CCL7 , Quimiocina CCL8 , Citocinas/biossíntese , Ésteres/síntese química , Ésteres/metabolismo , Ésteres/farmacologia , Humanos , Técnicas In Vitro , Interleucina-4/antagonistas & inibidores , Interleucina-4/biossíntese , Interleucina-5/antagonistas & inibidores , Interleucina-5/biossíntese , Interleucina-8/antagonistas & inibidores , Interleucina-8/biossíntese , Fígado/metabolismo , Pulmão/metabolismo , Proteínas Quimioatraentes de Monócitos/antagonistas & inibidores , Proteínas Quimioatraentes de Monócitos/biossíntese , Ovinos , Tiazóis/metabolismo , Tiazóis/farmacologia , Triazinas/metabolismo , Triazinas/farmacologiaRESUMO
This communication describes the synthesis and in vitro PDE4 inhibitory activity of a novel series of imidazol-2-one and 2-cyanoiminoimidazole derivatives. The compounds described were also tested in in vivo models to evaluate their anti-inflammatory activity after topical administration as well as their gastro-intestinal side effects. Several compounds proved to be potent PDE4 inhibitors and some 2-cyanoiminoimidazoles showed less pronounced gastro-intestinal side effects than reference compounds but maintained anti-inflammatory activity after topical administration.
