PEPTIDE ALDEHYDE INHIBITORS OF THE KALLIKREINS - AN INVESTIGATION OF SUBSITE INTERACTIONS WITH TRIPEPTIDES CONTAINING STRUCTURAL VARIATIONSAT THE AMINO-TERMINUS

A series of tripeptide aldehyde derivatives containing variations at t he P3 subsite and the amino terminus has been prepared and evaluated f or trypsin-like serine protease inhibition. These compounds exhibit st rong in vitro inhibition of human plasma kallikrein (HPK), porcine pan creatic kallikrein (PPK) and human plasmin (HP). As suspected from an examination of a related crystal structure, the presence of a hydropho bic residue (adamantyl) at the amino terminus dramatically improves th e binding to PPK. The adamantyl group, however, represents a peak in b inding; larger residues cause the binding to be reduced, and thus are less well accommodated in this subsite. Although both HP and HPK also can accept large molecular volume at the amino terminus, they do not e xhibit the same preference for large residues at this subsite that is demonstrated by PPK. Selectivity differences also are observed with P3 subsite substitution; with PPK preferring a bulky, but compact side-c hain (t-butyl) and HP and HPK preferring a more extended (e.g. benzyl) group.