title: A new development of matrix metalloproteinase inhibitors: twin hydroxamic acids as potent inhibitors of MMPs.
abstract: Starting from the observation that the CbzNH(CH2)2 side chain of the potent MMP-2/MMP-14 inhibitor, benzyl-(3R)-4-(hydroxyamino)-3-[isopropoxy(1,1'-biphenyl-4-yl-sulfonyl)amino]-4-oxobutylcarbamate, (R)-1 lies in a hydrophobic region (S1) exposed to the solvent of the protease active site, we hypothesized that an aminoethylcarboxamido chain structurally related to that of (R)-1 might be an useful tool to bind another linker stretching out from the protein. This would be able to interact either with a enzyme region adjacent to the active site, or with other molecules of matrix metalloproteinases (MMPs), or other proteins of the extracellular matrix (ECM) that may be involved in the enzyme activation. On these basis we describe new dimeric compounds of type 2, twin hydroxamic acids, obtained by the joint of two drug entities of (R)-1 linked in P1 by extendable semirigid linkers. Type 2 compounds are potentially able to undergo more complex inhibitor-enzyme interactions than those occurring with monomeric compounds of type 1, thus influencing positively the potency, selectivity and/or cytotoxicity of the new compounds.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Pisa, Via Bonanno, 6, 56126 Pisa, Italy. aros@farm.unipi.it
authors.forename: Armando
authors.initials: A
authors.lastname: Rossello
authors.forename: Elisa
authors.initials: E
authors.lastname: Nuti
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Catalani
authors.forename: Paolo
authors.initials: P
authors.lastname: Carelli
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Orlandini
authors.forename: Simona
authors.initials: S
authors.lastname: Rapposelli
authors.forename: Tiziano
authors.initials: T
authors.lastname: Tuccinardi
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Atkinson
authors.forename: Gillian
authors.initials: G
authors.lastname: Murphy
authors.forename: Aldo
authors.initials: A
authors.lastname: Balsamo
mesh_terms: D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D007202:Indicators and Reagents; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D007202:Indicators and Reagents; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2