title: Design, synthesis and biological evaluation of 5-hydroxy, 5-substituted-pyrimidine-2,4,6-triones as potent inhibitors of gelatinases MMP-2 and MMP-9.
abstract: Matrix metalloproteinases (MMPs) are attractive biological targets that play a key role in many physiopathological processes such as degradation of extracellular matrix proteins, release and cleavage of cell-surface receptors, tumour progression, homeostatic regulation and innate immunity. A series of 5-hydroxy, 5-substituted pyrimidine-2,4,6-triones were rationally designed, prepared and tested as inhibitors of gelatinases MMP-2 and MMP-9 and collagenase MMP-8. On one side, the presence of the 5-hydroxyl group, that represents an typical feature of this class of compounds, ensured an attractive pharmacokinetic profile while on the other suitably substituted biaryl molecular fragments, attached to position 5 through a ketomethylene linker, guaranteed favourable interaction in the deep region of the S(1)' enzymatic subsite. This rational design led to the discovery of highly potent MMP inhibitors. In particular, biphenyl derivatives bearing at the para position COCH(3) and OCF(3) substituents permitted to inhibit gelatinases MMP-2 and MMP-9, with IC(50) values as low as 30 nM and 21 nM, respectively, whereas the introduction at the same position of the bulkier SO(2)CH(3) group afforded a potent collagenase MMP-8 inhibitor with an IC(50) value equal to 66 nM. Molecular docking simulations allowed us to elucidate key interactions driving the binding of the top active compounds towards their preferred MMP target.
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Bari Aldo Moro, via Orabona 4, I-70125 Bari, Italy. orazio.nicolotti@uniba.it
authors.forename: Orazio
authors.initials: O
authors.lastname: Nicolotti
authors.forename: Marco
authors.initials: M
authors.lastname: Catto
authors.forename: Ilenia
authors.initials: I
authors.lastname: Giangreco
authors.forename: Maria
authors.initials: M
authors.lastname: Barletta
authors.forename: Francesco
authors.initials: F
authors.lastname: Leonetti
authors.forename: Angela
authors.initials: A
authors.lastname: Stefanachi
authors.forename: Leonardo
authors.initials: L
authors.lastname: Pisani
authors.forename: Saverio
authors.initials: S
authors.lastname: Cellamare
authors.forename: Paolo
authors.initials: P
authors.lastname: Tortorella
authors.forename: Fulvio
authors.initials: F
authors.lastname: Loiodice
authors.forename: Angelo
authors.initials: A
authors.lastname: Carotti
mesh_terms: D001463:Barbiturates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008958:Models, Molecular; D015394:Molecular Structure; D012709:Serum Albumin / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D001463:Barbiturates; D004791:Enzyme Inhibitors; D012709:Serum Albumin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9