Bis-Substituted Malonic Acid Hydroxamate Derivatives as Inhibitors of Human Neutrophil Collagenase (MMP8)

• Published in: Journal of medicinal chemistry 1998-07, Vol.41 (16), p.3041-3047
• Main Authors: Graf von Roedern, Erich, Brandstetter, Hans, Engh, Richard A, Bode, Wolfram, Grams, Frank, Moroder, Luis
• Format: Article
• Language: English
• Subjects: Analytical, structural and metabolic biochemistry; Binding Sites; Biological and medical sciences; Collagenases - metabolism; Crystallography, X-Ray; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Humans; Hydrolases; Hydroxamic Acids - chemical synthesis; Hydroxamic Acids - chemistry; Hydroxamic Acids - metabolism; Hydroxamic Acids - pharmacology; Malonates - chemical synthesis; Malonates - chemistry; Malonates - metabolism; Malonates - pharmacology; Matrix Metalloproteinase 8; Matrix Metalloproteinase Inhibitors; Models, Molecular; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm980112p

Malonic acid hydroxamate derivatives bis-substituted at the methylene group were synthesized as potential nonpeptidic inhibitors of human neutrophil collagenase (MMP8). The presence of an aromatic residue both at the C2 malonic acid position and in the C-terminal tail for hydrophobic interactions with the surface-exposed S1 binding site and the S1‘ pocket of the enzyme, respectively, was found to be sufficient for submicromolar inhibition potencies. For optimal insertion of the aryl amide group into the hydrophobic S1‘ pocket, spacing of the C-terminal phenyl group by at least a 3C-chain was required. In view of these results the achiral indan-2,2-dicarboxylic acid was used to mimic the 2-benzyl-2-methylmalonic acid residue, and its derivatization to the 3-phenylpropyl amide hydroxamate produced a potent, achiral, low-mass inhibitor of MMP8 (K i = 0.3 μM), the binding mode of which was unambiguously determined by X-ray crystallographic analysis.