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].

Coping with Asthma

Coping with Asthma

If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

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