Design and Synthesis of Malonic Acid-Based Inhibitors of Human Neutrophil Collagenase (MMP8)

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.

The 1.8-Å Crystal Structure of a Matrix Metalloproteinase 8-Barbiturate Inhibitor Complex Reveals a Previously Unobserved Mechanism for Collagenase Substrate Recognition

“…Additional optimization approaches are suggested by kinetic analyses of earlier x-ray structures of MMPs with peptidic, hydroxamic, and malonic acid-based inhibitors (2,26,27,45), whereby significant improvement in binding affinity is achieved by better filling the respective binding pockets (see Ref. 46 for a comprehensive review of these approaches).…”

Multidimensional Contribution of Matrix Metalloproteinases to Atherosclerotic Plaque Vulnerability: Multiple Mechanisms of Inhibition to Promote Stability

“…Advanced biochemical methods have produced selective inhibitors of MMP-1, 2, 3, 8, 9, 12, and 13, but few have been tested in animal models thus far [157,158,159,160,161,162,163,164,165,166,167,168,169,170,171]. Increased collagen was noted in the plaques of ApoE knockout mice treated with an MMP-13 inhibitor, a marker of plaque stability, but no change in plaque burden could be appreciated [170].…”

Carbon‐11 labelling of an N‐sulfonylamino acid derivative: a potential tracer for MMP‐2 and MMP‐9 imaging

“…The carboxylic group is able to participate in the chelation of the zinc atom, the presence of the sulfonyl group provides the hydrogen bonds 35,36 and the benzoyl aminobenzene side chain makes hydrophobic contacts with the S'1 subsite of the enzyme. [37][38][39][40] Furthermore, analogues of compound 7 have demonstrated selective gelatinases inhibition in vitro and anti-tumour activity in mice after oral administration. 29 The synthesis of 7 was conducted according to the preparation of other biphenyl-N-sulfonylamino acid derivatives described by Tamura et al…”