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
The current therapy for hepatitis C virus (HCV) infection has limited efficacy, in particular against the genotype 1 virus, and a range of side effects. In this context of high unmet medical need, more efficacious drugs targeting HCV nonstructural proteins are of interest. Here we describe 2'-deoxy-2'-spirocyclopropylcytidine (5) as a new inhibitor of the HCV NS5B RNA-dependent RNA polymerase, displaying an EC(50) of 7.3 µM measured in the Huh7-Rep cell line and no associated cytotoxicity (CC(50) > 98.4 µM). Computational results indicated high similarity between 5 and related HCV inhibiting nucleosides. A convenient synthesis was devised, facilitating synthesis of multigram quantities of 5. As the exposure measured after oral administration of 5 was found to be limited, the 3'-mono- and 3',5'-diisobutyryl ester prodrugs 20 and 23, respectively, were evaluated. The oral dosing of 23 led to substantially increased exposure to 5 in both rats and dogs.