title: MMP inhibition by barbiturate homodimers.
abstract: We have studied some homodimeric compounds derived from 5-homopiperazine substituted pyrimidine triones (barbiturates) with linkers in the range 2-20 carbon atoms. The compounds were designed to be capable of resisting absorption, to be stable in the gut and to maintain inhibitory potency against gelatinases and related function. The compounds were then assessed for inhibitory potency against a panel of MMPs (1, 2, 8, 9 and 13). The dimer compounds had similar potency and selectivity to the homopiperazine barbiturate monomer class. At 100 nM, selected dimers significantly inhibited cancer cell invasion in a matrigel assay using Caco-2 cells stimulated by hepatic growth factor. Finally, selected dimers showed adequate stability in simulated intestinal fluid to suggest the capacity to transit to the colon.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity College, Dublin 2, Ireland.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Marek W
authors.initials: MW
authors.lastname: Radomski
authors.forename: Carlos
authors.initials: C
authors.lastname: Medina
authors.forename: John F
authors.initials: JF
authors.lastname: Gilmer
mesh_terms: D001463:Barbiturates / Q000737:chemistry* / Q000494:pharmacology; D018938:Caco-2 Cells; D019281:Dimerization; D004355:Drug Stability; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D061965:Matrix Metalloproteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D020782:Matrix Metalloproteinases / Q000378:metabolism*
chemical_list: D001463:Barbiturates; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases