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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
23
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pubmed:dateCreated |
2007-11-6
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pubmed:abstractText |
Explorations in the pyrimidinetrione series of MMP-13 inhibitors led to the discovery of a series of spiro-fused compounds that are potent and selective inhibitors of MMP-13. While other spiro-fused motifs are hydrolytically unstable, presumably due to electronic destabilization of the pyrimidinetrione ring, the spiropyrrolidine series does not share this liability. Greater than 100-fold selectivity versus other MMP family members was achieved by incorporation of an extended aryl-heteroaryl P1'group. When dosed as the sodium salt, these compounds displayed excellent oral absorption and pharmacokinetic properties. Despite the selectivity, a representative of this series produced fibroplasia in a 14 day rat study.
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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 |
Dec
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pubmed:issn |
1464-3405
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pubmed:author |
pubmed-author:AntipasAmy SAS,
pubmed-author:DanleyDennis EDE,
pubmed-author:DattaKaushikK,
pubmed-author:DownsJames TJT,
pubmed-author:EisenbeisShaneS,
pubmed-author:EskraJames DJD,
pubmed-author:Freeman-CookKevin DKD,
pubmed-author:GarmeneDavid JDJ,
pubmed-author:GreerElaine MEM,
pubmed-author:GriffithsRichard JRJ,
pubmed-author:GuzmanRobertoR,
pubmed-author:HardinkJoel RJR,
pubmed-author:JanatFouadF,
pubmed-author:JonesChristopher SCS,
pubmed-author:LairdEllen RER,
pubmed-author:LirasJennifer LJL,
pubmed-author:Lopresti-MorrowLori LLL,
pubmed-author:MartinelliGary JGJ,
pubmed-author:MitchellPeter GPG,
pubmed-author:NoeMark CMC,
pubmed-author:PanditJayvardhanJ,
pubmed-author:ReillyUsa DUD,
pubmed-author:ReiterLawrence ALA,
pubmed-author:RobertsonDonaldD,
pubmed-author:Vaughn-BowserMarcie LML,
pubmed-author:Wolf-GouvieaLilli ALA,
pubmed-author:YocumSue ASA
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pubmed:issnType |
Electronic
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pubmed:day |
1
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pubmed:volume |
17
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
6529-34
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pubmed:meshHeading |
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pubmed:year |
2007
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pubmed:articleTitle |
Potent, selective spiropyrrolidine pyrimidinetrione inhibitors of MMP-13.
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pubmed:affiliation |
Pfizer Global Research & Development, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA. Kevin.Freeman-cook@pfizer.com
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pubmed:publicationType |
Journal Article,
Comparative Study
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