ANIONIC-MEDIATED AND LIPOPHILIC-MEDIATED SURFACE BINDING INHIBITORS OF HUMAN-LEUKOCYTE ELASTASE

We report the synthesis of a series of diphenylmethane-based oligomers containing anionic and lipophilic functionalities that are potent inh ibitors of human leukocyte elastase (HLE). The enzyme inhibition is re gulated by the size of the oligomer, as well as, the number of charges . Lipophilicity is an important element in determining potency and spe cificity against other basic enzymes. Compounds whose scaffolds contai n three phenoxyacetic acid groups and three alkyl ethers are competiti ve and specific inhibitors of HLE with K-i 20 nM. The mechanism of act ion of this class of compounds is believed to involve multidendate int eractions with the surface of HLE near the active site which prevents substrate access to the catalytic site.