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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
22
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pubmed:dateCreated |
1999-12-17
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pubmed:abstractText |
The synthesis and enzyme inhibition data for a series of thiazine- and thiazepine-based matrix metalloproteinase (MMP) inhibitors are described. The thiazine- and thiazepine-based inhibitors were discovered by optimization of hetererocyclic sulfonamide-based inhibitors. The most potent series of inhibitors was obtained by modification of the amino acid D-penicillamine. This amino acid provides a gem-dimethyl group on the thiazine or thiazepine ring which has a dramatic effect on the in vitro potency of this series. In particular, the sulfide 4a and the sulfone 5a were potent, broad-spectrum inhibitors of the MMPs with IC(50)'s against MMP-1 of 0.8 and 1.9 nM, respectively. The binding mode of this novel thiazepine-based series of MMP inhibitors was established based on X-ray crystallography of the complex of stromelysin and 4a.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Nov
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pubmed:issn |
0022-2623
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pubmed:author |
pubmed-author:AlmsteadN GNG,
pubmed-author:BradleyR SRS,
pubmed-author:DunawayC MCM,
pubmed-author:EYWW,
pubmed-author:HyndB ABA,
pubmed-author:JanuszM JMJ,
pubmed-author:KAON CNC,
pubmed-author:MielingG EGE,
pubmed-author:NatchusM GMG,
pubmed-author:PikusJJ,
pubmed-author:TaiwoY OYO,
pubmed-author:WilliamsL ELE
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pubmed:issnType |
Print
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pubmed:day |
4
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pubmed:volume |
42
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
4547-62
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pubmed:dateRevised |
2006-11-15
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pubmed:meshHeading |
pubmed-meshheading:10579818-Crystallography, X-Ray,
pubmed-meshheading:10579818-Cyclic S-Oxides,
pubmed-meshheading:10579818-Drug Design,
pubmed-meshheading:10579818-Enzyme Inhibitors,
pubmed-meshheading:10579818-Metalloendopeptidases,
pubmed-meshheading:10579818-Models, Molecular,
pubmed-meshheading:10579818-Structure-Activity Relationship,
pubmed-meshheading:10579818-Thiazepines,
pubmed-meshheading:10579818-Thiazines
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pubmed:year |
1999
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pubmed:articleTitle |
Design, synthesis, and biological evaluation of potent thiazine- and thiazepine-based matrix metalloproteinase inhibitors.
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pubmed:affiliation |
Procter and Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Road, Mason, Ohio 45040, USA.
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pubmed:publicationType |
Journal Article
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