In silico scaffold evaluation and solid phase approach to identify new gelatinase inhibitors.

Alessandra Topai, Perla Breccia, Franco Minissi, Alessandro Padova, Stefano Marini, Ilaria Cerbara

Colosseum Combinatorial Chemistry Centre for Technology (C4T SCarl), Via della Ricerca Scientifica snc, I-00133 Rome, Italy. alessandra.topai@uniroma2.it

Bioorganic & medicinal chemistry 2012 Apr 1

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Among matrix metalloproteinases (MMPs), gelatinases MMP-2 (gelatinase A) and MMP-9 (gelatinase B) play a key role in a number of physiological processes such as tissue repair and fibrosis. Many evidences point out their involvement in a series of pathological events, such as arthritis, multiple sclerosis, cardiovascular diseases, inflammatory processes and tumor progression by degradation of the extracellular matrix. To date, the identification of non-specific MMP inhibitors has made difficult the selective targeting of gelatinases. In this work we report the identification, design and synthesis of new gelatinase inhibitors with appropriate drug-like properties and good profile in terms of affinity and selectivity. By a detailed in silico protocol and innovative and versatile solid phase approaches, a series of 4-thiazolydinyl-N-hydroxycarboxyamide derivatives were identified. In particular, compounds 9a and 10a showed a potent inhibitory activity against gelatinase B and good selectivity over the other MMP considered in this study. The identified compounds could represent novel potential candidates as therapeutic agents. Copyright © 2012 Elsevier Ltd. All rights reserved.

Citation

Alessandra Topai, Perla Breccia, Franco Minissi, Alessandro Padova, Stefano Marini, Ilaria Cerbara. In silico scaffold evaluation and solid phase approach to identify new gelatinase inhibitors. Bioorganic & medicinal chemistry. 2012 Apr 1;20(7):2323-37