DIAMINIC CARBONATES, A NEW CLASS OF ANTIINFLAMMATORY COMPOUNDS - THEIR BIOLOGICAL CHARACTERIZATION AND MODE OF ACTION

Taking advantage of a standard assay on mouse LM cells (murine fibrobl ast-like cells), we found that several diaminic carbonates, a new clas s of organic compounds synthesized in our laboratories, were able to i nhibit human tumor necrosis factor alpha (huTNF-alpha)-induced cytotox icity in a dose-dependent manner. Structure-function relationship stud ies indicated precise structural requirements for compounds being acti ve as huTNF alpha inhibitors. ITF1779, one of the most active compound s in inhibiting huTNF alpha-induced cytotoxicity, was selected for fur ther studies. In vitro experiments showed that ITF1779 inhibited not o nly huTNF alpha-induced cytotoxicity on LM cells but also another resp onse of the same cells, interleukin-1-induced interleukin-6 production . Receptor-binding studies performed under nonequilibrium conditions a nd morphologic evidence of vacuole formation in cells treated with hig h concentrations of ITF1779 showed that the effects were strikingly si milar to those of chloroquine, a lysosomotropic agent. Consistent with a mechanism of action of diaminic carbonates closely matching that of chloroquine are some structural similarities between the two classes of compounds, in particular their both being diprotic weak bases. More over, ITF1779 was shown to be active in vivo because it afforded prote ction against lipopolysaccharide-induced shock in mice, a systemic inf lammatory response crucially dependent on tumor necrosis factor alpha production.