Inhibition of P-selectin specific cell adhesion by a low molecular weight, non-carbohydrate compound, KF38789

Objective and design: P-selectin is a cell adhesion molecule of the selectin family. This study evaluated the effects of novel, low molecular weight P-selectin inhibitors in a cell adhesion assay and a murine model of peritonitis. Materials: U937 or 14L60 was used for cell adhesion assay. Human polymorphonuclear cells were studied for the production of superoxide. BALB/c mice were used for the in vivo study. Treatment: The thioglycollate (TG)-induced accumulation of leukocytes in mice was measured 6 h after the treatment. KF38789 or antibody (1 mg/kg) was injected intravenously prior to TG injection and at 3 h following initial injection. Results: Low molecular weight, non-carbohydrate inhibitors against P-selectin- mediated cell adhesion were tested. One of the most potent inhibitors, KF38789, inhibited the binding of U937 cells to immobilized P-selectin immunoglobulin G chimeric protein (P-selectin-Ig) with an IC50 value of 1.97 muM. Cell adhesion to both E-selectin-Ig and L-selectin-Ig were not affected even by 100 muM of KF38789. Moreover, Y,F38789 inhibited P-selectin-induced superoxide production from human polymorphonuclear cells. Intravenously injected KF38789 significantly inhibited the TG-induced accumulation of leukocytes in the mouse peritoneal cavity (p < 0.01). Conclusion: A novel low molecular weight compound, KF38789, specifically inhibited P-selectin-dependent cell adhesion and the leukocyte recruitment in mouse peritonitis.