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

Colosseum Combinatorial Chemistry Centre for Technology (C4T SCarl), Via della Ricerca Scientifica snc, I-00133 Rome, Italy.
Bioorganic & medicinal chemistry (Impact Factor: 2.79). 02/2012; 20(7):2323-37. DOI: 10.1016/j.bmc.2012.02.010
Source: PubMed


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.

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