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 R 2 possessing an appropriate geometry, steric bulkiness and lipophilicity, is able to improve potency, in the subnanomolar range on MMP-2, and to give...

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Veröffentlicht in:Bioorganic & medicinal chemistry letters 2005-03, Vol.15 (5), p.1321-1326
Hauptverfasser: Rossello, Armando, Nuti, Elisa, Carelli, Paolo, Orlandini, Elisabetta, Macchia, Marco, Nencetti, Susanna, Zandomeneghi, Maurizio, Balzano, Federica, Uccello Barretta, Gloria, Albini, Adriana, Benelli, Roberto, Cercignani, Giovanni, Murphy, Gillian, Balsamo, Aldo
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Sprache:eng
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Zusammenfassung:Structural manipulation of the pharmacophoric model of type A selective MMP inhibitors (MMPi), obtained by the insertion of some alkyl substituents R 2 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 under the micromolar range. Structural manipulation of the pharmacophoric model of type A selective MMP inhibitors (MMPi), obtained by the insertion of some alkyl substituents R 2 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2005.01.024