Jun Wang, Carlos Medina, Marek W. Radomski, John F. Gilmer, N-subsituted homopiperazine barbiturates as gelatinase inhibitors, Bioorganic & Medicinal Chemistry, 19, 16, 2011, 4985-4999
Bioorganic & Medicinal Chemistry; 19; 16;
Matrix metalloproteinases are implicated in a wide range of pathophysiological processes and potent selective inhibitors for these enzymes continue to be eagerly sought. 5,5-Disubstituted barbiturates hold promise as inhibitor types being stable in vivo and relatively selective for the gelatinases (MMP-2 and MMP-9). In this paper we describe the synthesis of 5-piperazine and -homopiperazine substituted barbiturates. The activity of these compounds as gelatinase inhibitors was evaluated using supernatants from 12-O-tetradecanoylphorbol-13-acetate (PMA) - stimulated HT-1080 cells as well as using recombinant human MMPs. N-acyl homopiperazine compounds were found to be potent inhibitors of the gelatinases (range in nM) and generally more potent than the corresponding piperazine analogs. The panel of N-acyl homopiperazines was enlarged in order to exploit differences between the gelatinases at the S2’ site in order to design MMP-2- or MMP-9-selective inhibitors. Compounds in this group exhibited single digit nano-molar potency and some selectivity between the two enzymes. Representative potent compounds were effective inhibitors of cancer cell migration.
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