Matrix Metalloproteinases Inhibitors

MMPs have been implicated in the pulmonary remodeling processes that are common to both asthma and COPD [85]. The MMP profile in asthma differs from that in COPD with MMP-9 most closely associated with asthma and MMP-12 showing a strong connection to COPD. Work is progressing toward understanding the potential application of these MMPs as possible therapeutic targets in overcoming the pathophysiology of asthma and COPD [14,86-89].

Doxycycline inhibits MMP activity at sub-antimicrobial doses [90] and is the only MMP inhibitor widely available clinically, indicated for the treatment of periodontal disease [91]. Prescribed as an antibiotic, doxycycline is also used clinically to manage COPD. In August 2007, a clinical trial for the macrolide antibiotic azithromycin commenced to study its anti-inflammatory properties in people with COPD through the inhibition of the MMP-catalyzed breakdown of collagen [92]. Broad spectrum MMP inhibitors, such as marimastat (BB-2516), have performed poorly in clinical trials. Marimastat was shown to have considerable side effects and dose-limiting musculoskeletal toxicity. The mechanism of this toxicity has not been completely elucidated, though several proposals have been advanced [93].

More selective MMP inhibitors have been the focus of intense research recently. Analyses of multiple MMP co-crystal structures have shed light on the structural differences between different MMPs. A study of phosphinic peptide libraries afforded 29 with an MMP-12 Ki of 0.19 nM and selectivities > 200-fold against MMPs-3, 13, and 14 and > 1,000-fold over MMPs-1, 2, 7, 8, 9, and 11. Additionally, compounds like 29 do not inhibit other proteases such as angiotensin-converting enzyme, neutral endopeptidase, and tumor necrosis factor a (TNFa) converting enzyme (TACE) (Ki >100 p.M) [94]. A recent patent application claims selective inhibitors of MMPs, especially MMP-12, and presents 30 as a potent inhibitor of MMP-12 with > 500-fold selectivity for MMP-12 over MMP-3 and TACE [95].

PF-00356231 (31) has been co-crystallized with MMP-12. Although it is not selective for MMP-12, it is an example of a non-zinc-chelating MMP inhibitor. Within this study, acetohydroxamate, added to the crystallization solutions to aid protein stability, stabilized a ternary complex with 31 and the protein through chelation with the Zn2+ ion [96]. The design of non-zinc-chelating MMP inhibitors is aimed at identifying more selective compounds [97,98].

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