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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
14
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pubmed:dateCreated |
2005-6-24
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pubmed:abstractText |
A series of 3-hydroxy-3-methylpipecolic hydroxamate inhibitors of MMP-13 and aggrecanase was designed based on the observation of increased aggrecanase activity with substitution at the 3-position of the piperidine ring. Potency versus aggrecanase was optimized by modification of the benzyloxyarylsulfonamide group that binds in the S1' pocket. These compounds also possess markedly improved bioavailability and lower metabolic clearance compared to analogous 3,3-dimethyl-5-hydroxypipecolic hydroxamates. These improvements are attributed to lowered lipophilicity proximal to the metabolically labile hydroxamic acid. Synthesis, structure activity relationships, and in vivo efficacy data are described.
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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 |
Jul
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pubmed:issn |
0960-894X
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pubmed:author |
pubmed-author:BarberiaJohn TJT,
pubmed-author:BlivenMarcia AMA,
pubmed-author:CartyThomas JTJ,
pubmed-author:LirasJennifer LJL,
pubmed-author:Lopresti-MorrowLoriL,
pubmed-author:MitchellPeter GPG,
pubmed-author:NatarajanVijayalakshmiV,
pubmed-author:NoeMark CMC,
pubmed-author:OtternessIvanI,
pubmed-author:ReevesLisa MLM,
pubmed-author:SnowSheri LSL,
pubmed-author:SweeneyFrancis JFJ,
pubmed-author:VaughnMarcieM,
pubmed-author:Wolf-GouveiaLilli ALA,
pubmed-author:YocumSue ASA
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pubmed:issnType |
Print
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pubmed:day |
15
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pubmed:volume |
15
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
3385-8
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pubmed:dateRevised |
2006-11-15
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pubmed:meshHeading |
pubmed-meshheading:15953722-Administration, Oral,
pubmed-meshheading:15953722-Animals,
pubmed-meshheading:15953722-Collagenases,
pubmed-meshheading:15953722-Drug Design,
pubmed-meshheading:15953722-Endopeptidases,
pubmed-meshheading:15953722-Humans,
pubmed-meshheading:15953722-Hydroxamic Acids,
pubmed-meshheading:15953722-Matrix Metalloproteinase 13,
pubmed-meshheading:15953722-Molecular Structure,
pubmed-meshheading:15953722-Pipecolic Acids,
pubmed-meshheading:15953722-Protease Inhibitors,
pubmed-meshheading:15953722-Structure-Activity Relationship
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pubmed:year |
2005
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pubmed:articleTitle |
Discovery of 3-OH-3-methylpipecolic hydroxamates: potent orally active inhibitors of aggrecanase and MMP-13.
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pubmed:affiliation |
Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton CT 06340, USA. mark.c.noe@pfizer.com
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pubmed:publicationType |
Journal Article
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