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 have been implicated in various disease processes. Different classes of MMP inhibitors, including hydroxamic acids, phosphinic acids and thiols, have been previously described. Most of these mimic peptides and most likely bind in a similar way to the corresponding peptide substrates. Here we describe pyrimidine-triones as a completely new class of metalloprotease inhibitors. While the pyrimidine-trione template is used as the zinc-chelating moiety, the substituents have been optimized to yield inhibitors comparable in their 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).
Grams
F
F
Discovery Technologies, Preclinical Research Pharma, F.Hoffmann-LaRoche AG, Basel, Switzerland.
Brandstetter
H
H
D'Alò
S
S
Geppert
D
D
Krell
H W
HW
Leinert
H
H
Livi
V
V
Menta
E
E
Oliva
A
A
Zimmermann
G
G
Gram
F
F
Brandstetter
H
H
D'Alò
S
S
Geppert
D
D
Krell
H W
HW
Leinert
H
H
Livi VMenta
E
E
Oliva
A
A
Zimmermann
G
G
D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D020128:Inhibitory Concentration 50; D020784:Matrix Metalloproteinase 8 / Q000737:chemistry / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry; D013329:Structure-Activity Relationship
D002614:Chelating Agents; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D011743:Pyrimidines; D020784:Matrix Metalloproteinase 8; C030986:pyrimidine