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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
6
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pubmed:dateCreated |
1997-5-1
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pubmed:abstractText |
Carboxyalkyl peptides containing a biphenylylethyl group at the P1' position were found to be potent inhibitors of stromelysin-1 (MMP-3) and gelatinase A (MMP-2), in the range of 10-50 nM, but poor inhibitors of collagenase (MMP-1). Combination of a biphenylylethyl moiety at P1', a tert-butyl group at P2', and a methyl group at P3' produced orally bioavailable inhibitors as measured by an in vivo model of MMP-3 degradation of radiolabeled transferrin in the mouse pleural cavity. The X-ray structure of a complex of a P1-biphenyl inhibitor and the catalytic domain of MMP-3 is described. Inhibitors that contained halogenated biphenylylethyl residues at P1' proved to be superior in terms of enzyme potency and oral activity with 2(R)-[2-(4'-fluoro-4-biphenylyl)ethyl]-4(S)-n-butyl-1,5-pentane dioic acid 1-(alpha(S)-tert-butylglycine methylamide) amide (L-758,354, 26) having a Ki of 10 nM against MMP-3 and an ED50 of 11 mg/kg po in the mouse pleural cavity assay. This compound was evaluated in acute (MMP-3 and IL-1 beta injection in the rabbit) and chronic (rat adjuvant-induced arthritis and mouse collagen-induced arthritis) models of cartilage destruction but showed activity only in the MMP-3 injection model (ED50 = 6 mg/kg iv).
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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 |
http://linkedlifedata.com/resource/pubmed/chemical/Collagenases,
http://linkedlifedata.com/resource/pubmed/chemical/Dipeptides,
http://linkedlifedata.com/resource/pubmed/chemical/Gelatinases,
http://linkedlifedata.com/resource/pubmed/chemical/Interleukin-1,
http://linkedlifedata.com/resource/pubmed/chemical/Matrix Metalloproteinase 1,
http://linkedlifedata.com/resource/pubmed/chemical/Matrix Metalloproteinase 2,
http://linkedlifedata.com/resource/pubmed/chemical/Matrix Metalloproteinase 3,
http://linkedlifedata.com/resource/pubmed/chemical/Metalloendopeptidases,
http://linkedlifedata.com/resource/pubmed/chemical/N-(1-carboxyethyl)-alpha-(2-phenylet...,
http://linkedlifedata.com/resource/pubmed/chemical/Protease Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Transferrin,
http://linkedlifedata.com/resource/pubmed/chemical/Zinc
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pubmed:status |
MEDLINE
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pubmed:month |
Mar
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pubmed:issn |
0022-2623
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pubmed:author |
pubmed-author:AxelM GMG,
pubmed-author:BeckerJ WJW,
pubmed-author:BugianesiR LRL,
pubmed-author:CaldwellC GCG,
pubmed-author:ChapmanK TKT,
pubmed-author:ChristenA JAJ,
pubmed-author:DuretteP LPL,
pubmed-author:EsserC KCK,
pubmed-author:GirotraN NNN,
pubmed-author:HagmannW KWK,
pubmed-author:HarrisonR KRK,
pubmed-author:KopkaI EIE,
pubmed-author:LanzaT JTJ,
pubmed-author:LevorseD ADA,
pubmed-author:MacCossMM,
pubmed-author:MarcyA IAI,
pubmed-author:McDonnellJJ,
pubmed-author:MooreV LVL,
pubmed-author:NiedzwieckiLL,
pubmed-author:OlszewskiJ MJM,
pubmed-author:OwensK AKA,
pubmed-author:PonpipomM MMM,
pubmed-author:SaphosCC,
pubmed-author:SimeoneJ PJP,
pubmed-author:ViscoD MDM
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pubmed:issnType |
Print
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pubmed:day |
14
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pubmed:volume |
40
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pubmed:owner |
NLM
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pubmed:authorsComplete |
N
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pubmed:pagination |
1026-40
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pubmed:dateRevised |
2011-11-17
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pubmed:meshHeading |
pubmed-meshheading:9083493-Animals,
pubmed-meshheading:9083493-Arthritis,
pubmed-meshheading:9083493-Binding Sites,
pubmed-meshheading:9083493-Cartilage,
pubmed-meshheading:9083493-Collagenases,
pubmed-meshheading:9083493-Crystallography, X-Ray,
pubmed-meshheading:9083493-Dipeptides,
pubmed-meshheading:9083493-Disease Models, Animal,
pubmed-meshheading:9083493-Gelatinases,
pubmed-meshheading:9083493-Interleukin-1,
pubmed-meshheading:9083493-Magnetic Resonance Spectroscopy,
pubmed-meshheading:9083493-Matrix Metalloproteinase 1,
pubmed-meshheading:9083493-Matrix Metalloproteinase 2,
pubmed-meshheading:9083493-Matrix Metalloproteinase 3,
pubmed-meshheading:9083493-Metalloendopeptidases,
pubmed-meshheading:9083493-Mice,
pubmed-meshheading:9083493-Models, Molecular,
pubmed-meshheading:9083493-Molecular Structure,
pubmed-meshheading:9083493-Protease Inhibitors,
pubmed-meshheading:9083493-Rabbits,
pubmed-meshheading:9083493-Rats,
pubmed-meshheading:9083493-Recombinant Proteins,
pubmed-meshheading:9083493-Structure-Activity Relationship,
pubmed-meshheading:9083493-Transferrin,
pubmed-meshheading:9083493-Zinc
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pubmed:year |
1997
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pubmed:articleTitle |
Inhibition of stromelysin-1 (MMP-3) by P1'-biphenylylethyl carboxyalkyl dipeptides.
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pubmed:affiliation |
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065-0900, USA.
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pubmed:publicationType |
Journal Article
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