Bis-substituted malonic acid hydroxamate derivatives as inhibitors of human neutrophil collagenase (MMP8).
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 (Ki = 0.3 microM), the binding mode of which was unambiguously determined by X-ray crystallographic analysis.
Graf von Roedern
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E
Max-Planck-Institut für Biochemie, Am Klopferspitz 18A, D-82152 Martinsried, Germany, Department of Biotechnology, Boehringer Mannheim GmbH, D-82372 Penzberg, Germany.
Brandstetter
H
H
Engh
R A
RA
Bode
W
W
Grams
F
F
Moroder
L
L
D001665:Binding Sites; D017364:Collagenases / Q000378:metabolism; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008314:Malonates / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D020784:Matrix Metalloproteinase 8; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D008314:Malonates; D061965:Matrix Metalloproteinase Inhibitors; D017364:Collagenases; D020784:Matrix Metalloproteinase 8