A new development of matrix metalloproteinase inhibitors: twin hydroxamic acids as potent inhibitors of MMPs.
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.
Rossello
Armando
A
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Pisa, Via Bonanno, 6, 56126 Pisa, Italy. aros@farm.unipi.it
Nuti
Elisa
E
Catalani
Maria Pia
MP
Carelli
Paolo
P
Orlandini
Elisabetta
E
Rapposelli
Simona
S
Tuccinardi
Tiziano
T
Atkinson
Susan J
SJ
Murphy
Gillian
G
Balsamo
Aldo
A
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
D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D007202:Indicators and Reagents; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2