Abstract：
:The pathology of chronic dermal ulcers is characterized by excessive proteolytic activity which degrades extracellular matrix (required for cell migration) and growth factors and their receptors. The overexpression of MMP-3 (stromelysin-1) and MMP-13 (collagenase-3) is associated with nonhealing wounds, whereas active MMPs-1, -2, -9, and -14 are required for normal wound healing to occur. We describe the synthesis and enzyme inhibition profile of (3R)-3-[([(1S)-2,2-dimethyl-1-(([(1S)-2-methoxy-1-phenylethyl]amino)carbonyl)propyl]amino)carbonyl]-6-(3-methyl-4-phenylphenyl)hexanoic acid (UK-370,106, 7), which is a potent inhibitor of MMP-3 (IC(50) = 23 nM) with >1200-fold weaker potency vs MMP-1, -2, -9, and -14. MMP-13, which may also contribute to the pathology of chronic wounds, was inhibited about 100-fold less potently by compound 7. Compound 7 potently inhibited cleavage of [(3)H]-fibronectin by MMP-3 (IC(50) = 320 nM) but not cleavage of [(3)H]-gelatin by either MMP-2 or -9 (up to 100 microM). Compound 7 had little effect, at MMP-3 selective concentrations, on keratinocyte migration over a collagen matrix in vitro, which is a model of the re-epithelialization process. Following iv (rat) or topical administration to dermal wounds (rabbit), compound 7 was cleared rapidly (t(1/2) = 23 min) from plasma, but slowly (t(1/2) approximately 3 days) from dermal tissue. In a model of chronic dermal ulcers, topical administration of compound 7 for 6 days substantially inhibited MMP-3 ex vivo. These data suggest compound 7 is sufficiently potent to inhibit MMP-3-mediated matrix degradation while leaving unaffected cellular migration mediated by MMPs 1, 2, and 9. These properties make compound 7 a suitable candidate for progression to clinical trials in human chronic dermal wounds, such as venous ulcers.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Fray MJ,Dickinson RP,Huggins JP,Occleston NLdoi
10.1021/jm0308038keywords:
subject
Has Abstractpub_date
2003-07-31 00:00:00pages
3514-25issue
16eissn
0022-2623issn
1520-4804journal_volume
46pub_type
杂志文章abstract：:The inhibitory activity of 1058 inhibitors of the title enzymes has been formulated in 13 equations correlating chemical structure with inhibitory potency. Two types of regions in enzymes have been defined by means of pi and molar refractivity constants. The use of indicator variables has been extensively developed to...
journal_title：Journal of medicinal chemistry
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更新日期：2011-10-27 00:00:00
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pub_type： 杂志文章
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doi：10.1021/jm801385d
更新日期：2009-04-23 00:00:00
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更新日期：2013-08-22 00:00:00
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journal_title：Journal of medicinal chemistry
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doi：10.1021/jm00173a012
更新日期：1990-11-01 00:00:00
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更新日期：2013-09-26 00:00:00
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更新日期：2007-09-20 00:00:00
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更新日期：2008-07-24 00:00:00
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更新日期：1981-03-01 00:00:00
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更新日期：1999-01-14 00:00:00
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更新日期：2009-07-23 00:00:00
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