Novel 5,5-disubstitutedpyrimidine-2,4,6-triones as selective MMP inhibitors.
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.
Foley
L H
LH
Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. louise.foley@roche.com
Palermo
R
R
Dunten
P
P
Wang
P
P
D000818:Animals; D017364:Collagenases / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D020128:Inhibitory Concentration 50; D053509:Matrix Metalloproteinase 13; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020784:Matrix Metalloproteinase 8 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D061965:Matrix Metalloproteinase Inhibitors; D011744:Pyrimidinones; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases; C507081:Mmp13 protein, mouse; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020784:Matrix Metalloproteinase 8; D020780:Matrix Metalloproteinase 9