Document Report Card

ID: ALA1131458

Journal: J Med Chem

Title: Design and synthesis of malonic acid-based inhibitors of human neutrophil collagenase (MMP8).

Authors: Graf von Roedern E, Grams F, Brandstetter H, Moroder L.

Abstract: For most of the known synthetic inhibitors of matrix metalloproteinases (MMPs), a substrate-like binding mode was postulated on the basis of X-ray crystallographic structures of MMP/inhibitor complexes. Conversely, the malonic acid-based inhibitor (2R,S)-HONH-CO-CH(i-Bu)-CO-Ala-Gly-NH2 was found to bind in a surprisingly different manner. Using this compound as a new lead structure, the interaction sites with human neutrophil collagenase (MMP8) were optimized with a series of iteratively designed analogues and with the help of X-ray structural analysis of selected inhibitors to finally produce low molecular weight nonpeptidic compounds of 500-1000-fold improved inhibitory potency.

CiteXplore: 9464365

DOI: 10.1021/jm9706426