DESIGN AND SYNTHESIS OF MALONIC ACID-BASED INHIBITORS OF HUMAN NEUTROPHIL COLLAGENASE (MMP8)

For most of the known synthetic inhibitors of matrix metalloproteinase s (MMPs), a substrate-like binding mode was postulated on the basis of X-ray crystallographic structures of MMP/inhibitor complexes. Convers ely, the malonic acid-based inhibitor (2R,S)-HONH-CO-CH(i-Bu)-CO-Ala-G ly-NH2 was found to bind in a surprisingly different manner. Using thi s compound as a new lead structure, the interaction sites with human n eutrophil collagenase (MMP8) were optimized with a series of iterative ly designed analogues and with the help of X-ray structural analysis o f selected inhibitors to finally produce low molecular weight nonpepti dic compounds of 500-1000-fold improved inhibitory potency.