INHIBITION OF HUMAN NEUTROPHIL ELASTASE AND CATHEPSIN-G BY A BIPHENYLDISULFONIC ACID COPOLYMER

The sulfated polymer MDL 101,028 was found to be a potent inhibitor of both human neutrophil elastase (HNE) and human neutrophil cathepsin G (CatG). Cleavage of synthetic substrate by HNE was inhibited by MDL 1 01,028 with an IC50 of 40 nM, while CatG was inhibited with an IC50 of 80 nM. Degradation of a macromolecular connective tissue substrate (c artilage proteoglycan) by HNE or CatG was inhibited by MDL 101,028 wit h an IC50 of approximately 10 mu M. MDL 101,028 at concentrations of 4 , 10 and 25 mu M inhibited degradation of cartilage proteoglycan by hu man neutrophil lysate or stimulated human neutrophils by 54%, 70% and 79%, and 31%, 47% and 73%, respectively. Acute pulmonary injury result ing from the intratracheal (i.t.) instillation of HNE in rats was inhi bited by 48%, 90% and 90% al concentrations of MDL 101,028 of 1.1 mg/k g, 2.8 mg/kg and 11 mg/kg. The duration of action of the compound afte r i.t. instillation was between 2 and 4 h. These results suggest that sulfated polymers such as MDL 101,146 may be useful as inhibitors of H NE-mediated lung injury.