BIS-SUBSTITUTED MALONIC-ACID HYDROXAMATE DERIVATIVES AS INHIBITORS OFHUMAN NEUTROPHIL COLLAGENASE (MMP8)

Malonic acid hydroxamate derivatives bis-substituted at the methylene group were synthesized as potential nonpeptidic inhibitors of human ne utrophil collagenase (MMP8). The presence of an aromatic residue both at the C2 malonic acid position and in the C-terminal tail for hydroph obic interactions with the surface-exposed S1 binding site and the S1' pocket of the enzyme, respectively, was found to be sufficient for su bmicromolar inhibition potencies. For optimal insertion of the aryl am ide group into the hydrophobic S1' pocket, spacing of the C-terminal p henyl group by at least a SC-chain was required. In view of these resu lts the achiral indan-2,2-dicarboxylic acid was used to mimic the 2-be nzyl-2-methylmalonic acid residue, and its derivatization to the 3-phe nylpropyl amide hydroxamate produced a potent, achiral, low-mass inhib itor of MMP8 (K-i = 0.3 mu M), the binding mode of which was unambiguo usly determined by X-ray crystallographic analysis.