N-i-Propoxy-N-biphenylsulfonylaminobutylhydroxamic acids as potent and selective inhibitors of MMP-2 and MT1-MMP.
Structural manipulation of the pharmacophoric model of type A selective MMP inhibitors (MMPi), obtained by the insertion of some alkyl substituents R2 possessing an appropriate geometry, steric bulkiness and lipophilicity, is able to improve potency, in the subnanomolar range on MMP-2, and to give a good MMP inhibition on MMP-14 (MT1-MMP) in the designed MMPi of type C, while maintaining a good MMP-1/MMP-2 selectivity profile. The simultaneous inhibition of these two enzymes yields type C compounds, which are potent antiangiogenic agents, able to block a chemoinvasion model on HUVEC cells in the micromolar range.
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
Carelli
Paolo
P
Orlandini
Elisabetta
E
Macchia
Marco
M
Nencetti
Susanna
S
Zandomeneghi
Maurizio
M
Balzano
Federica
F
Uccello Barretta
Gloria
G
Albini
Adriana
A
Benelli
Roberto
R
Cercignani
Giovanni
G
Murphy
Gillian
G
Balsamo
Aldo
A
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D001485:Basement Membrane; D018929:Cell Culture Techniques / Q000379:methods; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology*; D061965:Matrix Metalloproteinase Inhibitors; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008968:Molecular Conformation; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D020533:Angiogenesis Inhibitors; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases