MATRIX METALLOPROTEINASE INHIBITORS - A STRUCTURE-ACTIVITY STUDY

Modifications around the dipeptide-mimetic core of a hydroxamic acid b ased matrix metalloproteinase inhibitor were studied. These variations incorporated a variety of natural, unnatural, and synthetic amino aci ds in addition to modifications of the P1' and P3' substituents. The r esults of this study indicate the following structural requirements: ( 1) Two key hydrogen bonds must be present between the enzyme and poten t substrates. (2) Potent inhibitors must possess strong zinc-binding f unctionalities. (3) The potential importance of the hydrophobic group at position R3 as illustrated by its ability to impart greater relativ e potency against stromelysin when larger hydrophobic groups are used. (4) Requirements surrounding the nature of the amino acid appear to b e more restrictive for stromelysin than for neutrophil collagenase, 72 kDa gelatinase, and 92 kDa gelatinase. These requirements may involve planar fused-ring aryl systems and possibly hydrogen-bonding capabili ties.