Design, Synthesis, Biological Evaluation, and NMR Studies of a New Series of Arylsulfones As Selective and Potent Matrix Metalloproteinase-12 Inhibitors

作者：Nuti Elisa; Panelli Laura; Casalini Francesca; Avramova Stanislava I; Orlandini Elisabetta; Santamaria Salvatore; Nencetti Susanna; Tuccinardi Tiziano; Martinelli Adriano; Cercignani Giovanni; D'Amelio Nicola; Maiocchi Alessandro; Uggeri Fulvio; Rossello Armando^*

来源：Journal of Medicinal Chemistry, 2009, 52(20): 6347-6361.

DOI：10.1021/jm900335a

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 IC(50) 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.

• 出版日期2009-10-22