Design, synthesis, biological evaluation, and NMR studies of a new series of arylsulfones as selective and potent matrix metalloproteinase-12 inhibitors.
Overexpression of macrophage elastase (MMP-12), a member of the matrix metalloproteinases family, can be linked to tissue remodeling and degradation in some inflammatory processes, such as chronic obstructive pulmonary disease (COPD), emphysema, rheumatoid arthritis (RA), and atherosclerosis. On this basis, MMP-12 can be considered an attractive target for studying selective inhibitors that are useful in the development of new therapies for COPD and other inflammatory diseases. We report herein the design, synthesis, and in vitro evaluation of a new series of compounds, possessing an arylsulfonyl scaffold, for their potential as selective inhibitors of MMP-12. The best compound in the series showed an IC50 value of 0.2 nM, with good selectivity over MMP-1 and MMP-14. A docking study was carried out on this compound in order to investigate its binding interactions with MMP-12, and NMR studies on the complex with the MMP-12 catalytic domain were able to validate the proposed binding mode.
Dipartimento di Scienze Farmaceutiche, Università di Pisa, via Bonanno 6, 56126 Pisa, Italy.
Elisa
E
Nuti
Laura
L
Panelli
Francesca
F
Casalini
Stanislava I
SI
Avramova
Elisabetta
E
Orlandini
Salvatore
S
Santamaria
Susanna
S
Nencetti
Tiziano
T
Tuccinardi
Adriano
A
Martinelli
Giovanni
G
Cercignani
Nicola
N
D'Amelio
Alessandro
A
Maiocchi
Fulvio
F
Uggeri
Armando
A
Rossello
D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D053508:Matrix Metalloproteinase 12 / Q000737:chemistry; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D008968:Molecular Conformation; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D013450:Sulfones; D053508:Matrix Metalloproteinase 12