Substituted Xanthines, Pteridinediones, and Related Compounds as Potential Antiinflammatory Agents. Synthesis and Biological Evaluation of Inhibitors of Tumor Necrosis Factor α

A series of analogues of pentoxifylline metabolites were prepared in the purine, pteridine, [1,2,5]thiadiazolo[3,4-d]pyrimidine, and quinazoline ring systems and evaluated for their ability to inhibit the production of tumor necrosis factor-α (TNFα) in human peripheral blood monocytes stimulated with bacterial lipopolysaccharide (LPS). The more active compounds were also tested for inhibition of cyclic AMP phosphodiesterase type IV (PDE IV) from human neutrophils in order to help determine their mechanism of action. Selected compounds which showed good activity in the in vitro TNFα assay were evaluated in an in vivo LPS-induced leukopenia model in mice. The most potent compounds in the TNFα assay, 6, 31, and 58, inhibited TNFα production at an IC50 of approximately 5 μM for each. Compound 58 was a very poor inhibitor of PDE IV but was the most active at preventing the leukopenia induced by TNFα in mice, providing more than 60% protection at 50 mg/kg. Thus, compounds such as 58, which are good inhibitors of TNFα production but are devoid of PDE IV inhibitory properties, may have potential as new antiinflammatory agents.