SUBSTITUTED XANTHINES, PTERIDINEDIONES, AND RELATED-COMPOUNDS AS POTENTIAL ANTIINFLAMMATORY AGENTS - SYNTHESIS AND BIOLOGICAL EVALUATION OFINHIBITORS OF TUMOR-NECROSIS-FACTOR-ALPHA

A series of analogues of pentoxifylline metabolites were prepared in t he purine, pteridine, [1,2,5]thiadiazolo[3,4-d]pyrimidine, and quinazo line ring systems and evaluated for their ability to inhibit the produ ction of tumor necrosis factor-alpha (TNF alpha) in human peripheral b lood monocytes stimulated with bacterial lipopolysaccharide (LPS). The more active compounds were also tested for inhibition of cyclic AMP p hosphodiesterase type IV (PDE IV) from human neutrophils in order to h elp determine their mechanism of action. Selected compounds which show ed good activity in the in vitro TNF alpha assay were evaluated in an in vivo LPS-induced leukopenia model in mice. The most potent compound s in the TNF alpha assay, 6, 31, and 58, inhibited TNF alpha productio n at an IC50 of approximately 5 mu M for each. Compound 58 was a very poor inhibitor of PDE IV but was the most active at preventing the leu kopenia induced by TNF alpha in mice, providing more than 60% protecti on at 50 mg/kg. Thus, compounds such as 58, which are good inhibitors of TNF alpha production but are devoid of PDE IV inhibitory properties , may have potential as new antiinflammatory agents.