Effect of imidazo[1,2-α]pyrimidine derivatives on leukocyte function

Objective and Design: A series of six imidazo[1,2-α]pyrimidine (IP) derivatives were evaluated for their effects on leukocyte functions in vitro as well as on the inflammatory response induced by zymosan in the mouse air pouch.¶Materials and Subjects: Human neutrophils and murine peritoneal macrophages were used for in vitro assays. Mouse air pouch was performed in Swiss mice.¶Treatment: Test compounds were incubated with either human neutrophils or mouse peritoneal macrophages at concentrations not showing cytotoxic effects. For in vivo experiments, IPs were injected into the air pouch.¶Methods: Elastase and myeloperoxidase release, superoxide generation and LTB4 production were assayed in human neutrophils treated with different stimuli. Mouse peritoneal macrophages were stimulated with lipopolysaccharide (LPS), followed by determination of nitrite and PGE2 levels in supernatants. Zymosan was injected into six days-old mouse air pouches. Dunnett's t-test was employed for statistical analysis.¶Results: All IPs inhibited human neutrophil degranulation with IC50 values in the μM range. IP-1, IP-2 and IP-5 also decreased superoxide generation. In LPS-stimulated macrophages, IP-4 and IP-6 inhibited nitrite production with a moderate reduction in PGE2 generation. In addition, these two compounds at 100 nmol/pouch inhibited leukocyte migration and LTB4 levels in the exudate of the mouse air pouch.¶Conclusions: Imidazo[1,2-α]pyrimidines are a class of compounds with antiinflammatory potential.