Novel 5,5-disubstitutedpyrimidine-2,4,6-triones as selective MMP inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 11; no. 8; pp. 969 - 972
• Main Authors: Foley, Louise H, Palermo, Robert, Dunten, Pete, Wang, Ping
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 23.04.2001; Elsevier
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Collagenases - metabolism; Crystallography, X-Ray; General aspects; Humans; Inhibitory Concentration 50; Matrix Metalloproteinase 13; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 3 - metabolism; Matrix Metalloproteinase 8 - metabolism; Matrix Metalloproteinase 9 - metabolism; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases - metabolism; Medical sciences; Mice; Pharmacology. Drug treatments; Pyrimidinones - chemical synthesis; Pyrimidinones - pharmacology; Structure-Activity Relationship; Antineoplastic agent; Nitrogen heterocycle; Toxicity; Active site; Metalloendopeptidases; Selectivity; Harmlessness; Modeling; Structure activity relation; Six membered ring; Molecular model; Barbiturates; Chemical synthesis; Stromelysin 1; Enzyme; Rodentia; Benzene derivatives; Oral administration; Enzyme inhibitor; Inhibitor enzyme complex; X ray diffraction; In vitro; Gelatinase B; Gelatinase A; Peptidases; Vertebrata; Mammalia; Mouse; Animal; Neutrophil collagenase; Hydrolases
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(01)00104-4

The 5,5-disubstitutedpyrimidine-2,4,6-triones represent a new class of MMP inhibitors showing selectivity for the gelatinases A and B, collagenase-3, and human neutrophil collagenase. The SAR presented here is in good agreement with an X-ray structure of compound 5 bound to the catalytic domain of stromelysin-1. While of the barbiturate structural class, compound 5 did not show any toxic or sedative effects. The pyrimidine triones represent a new class of MMP inhibitor showing selectivity for gelatinases A and B, collagenase-3, and human neutrophil collagenase. A SAR is presented that is in good agreement with X-ray structures obtained with this class. While belonging to the barbiturate compound class the pyrimidine trione 5 did not show barbiturate-like activities.