Interleukin (IL)-5 regulates the growth, differentiation, and activation of eosinophils. When activated, eosinophils release an array of proinflammatory and cytotoxic products and act as prominent effector cells in the process of allergic
inflammation. Depriving eosinophils of
IL-5 may therefore represent a viable approach to treat allergic disorders. This study describes the identification of R146225, a novel six-substituted
azauracil derivative, as a potent, orally active inhibitor of
IL-5 biosynthesis, capable of reducing
pulmonary eosinophilia in mice. In vitro, R146225 inhibited
IL-5 protein formation by activated human whole blood (IC(50) = 34 nM), human peripheral blood mononuclear cells (IC(50) = 24 nM), and murine spleen cells (IC(50) = 6 nM). In contrast, the compound enhanced generation of
interferon-gamma and had little or no inhibitory effect on the production of
IL-2 and
IL-4. Reverse transcription-polymerase chain reaction analysis of stimulated whole blood cells indicated R146225's ability to down-regulate
IL-5 mRNA expression. In vivo p.o. administration of R146225 (2.5 mg/kg) to mice before an i.v. anti-CD3 antibody challenge reduced
IL-5 but enhanced
interferon-gamma serum levels, without affecting
IL-2 and
IL-4 production. Analogous to the in vitro results, R146225 suppressed splenic
IL-5 mRNA expression, while message levels of the other
cytokines remained unchanged. Moreover, p.o. dosing of R146225 (0.6-2.5 mg/kg) dose dependently reduced the pulmonary accumulation of eosinophils induced in mice by an intranasal instillation of Cryptococcus neoformans. Based on these data, R146225 may be useful in the
therapy of eosinophil-driven allergic conditions.