Pyrimidine-2,4,6-triones: A new effective and selective class of matrix metalloproteinase inhibitors

Matrix metalloproteinases (MMPs) are a family of zinc endopeptidases that h ave been implicated in various disease processes. Different classes of MMP inhibitors, including hydroxamic acids, phosphinic acids and thiols, have b een previously described. Most of these mimic peptides and most likely bind in a similar way to the corresponding peptide substrates. Here we desccrib e pyrimidine-triones as a completely new class of metalloprotease inhibitor s. While the pyrimidine-trione template is used as the zinc-chelating moiet y, the substituents have been optimized to yield inhibitors comparable in t heir inhibition efficiency of matrix metalloproteinases to hydroxamic acid derivatives such as batimastat. However, they are much more specific for a small subgroup of MMPs, namely the gelatinases (MMP-2 and MMP-9).