Linked Life Data

12152654

Source:http://linkedlifedata.com/resource/pubmed/id/12152654

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2002-8-2
pubmed:abstractText
Plasminogen activator inhibitor-1 (PAI-1), the primary physiological inhibitor of both tissue-type plasminogen activator and urokinase-type plasminogen activator in plasma, is a well established risk factor in thrombotic diseases. Reduction of active PAI-1 levels may lead to a decreased tendency of thrombosis. Compounds that can suppress pharmacologically active PAI-1 levels are therefore considered as putative drugs. In the present study, we describe the PAI-1 neutralizing properties and mechanism of a newly selected compound (i.e. fendosal, HP129) in comparison to four previously reported compounds (i. e. AR-H029953XX, XR1853, XR5118 and the peptide TVASS) using different assays. The inhibitory effect of these compounds on active PAl-1 was analyzed by a plasmin-coupled chromogenic assay (Coaset t-PA), direct chromogenic assays (t-PA, u-PA) and quantification of complex formation by ELISA, SDS-PAGE and surface plasmon resonance. Comparative evaluation of the obtained IC50 values reveals large differences [i.e. IC50 of 15 microM (HP129) vs. >1000 microM (XR5118) determined at 37 degrees C using SDS-PAGE] between the compounds studied. Importantly, the relative potency of the various compounds is also dependent on the method used (10 to 170-fold differences in IC50 values). Characterization of the PAI-1 forms (i.e. active, non-reactive and substrate) generated upon inactivation reveals that the newly described compound HP129 induces a unique pathway (i.e. active to non-reactive conversion via a substrate-behaving intermediate) of inactivation compared to the other compounds. Taken together, these data strongly suggest that the various compounds act through different mechanisms. In addition, the results stress the necessity for a careful selection of the method used for the evaluation of PAI-1 inhibitors, preferably requiring a panel of screening methods.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/AR-H029953XX, http://linkedlifedata.com/resource/pubmed/chemical/Anticoagulants, http://linkedlifedata.com/resource/pubmed/chemical/Chlorphenamidine, http://linkedlifedata.com/resource/pubmed/chemical/Chromogenic Compounds, http://linkedlifedata.com/resource/pubmed/chemical/Nitro Compounds, http://linkedlifedata.com/resource/pubmed/chemical/Piperazines, http://linkedlifedata.com/resource/pubmed/chemical/Plasminogen Activator Inhibitor 1, http://linkedlifedata.com/resource/pubmed/chemical/Salicylic Acids, http://linkedlifedata.com/resource/pubmed/chemical/Serine Proteinase Inhibitors, http://linkedlifedata.com/resource/pubmed/chemical/XR 1853, http://linkedlifedata.com/resource/pubmed/chemical/XR 5118, http://linkedlifedata.com/resource/pubmed/chemical/fendosal
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0340-6245
pubmed:author
pubmed:issnType
Print
pubmed:volume
88
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
137-43
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
2002
pubmed:articleTitle
Characterization and comparative evaluation of a novel PAI-1 inhibitor.
pubmed:affiliation
Laboratory for Pharmaceutical Biology and Phytopharmacology, Faculty of Pharmaceutical Sciences, Katholieke Universiteit Leuven, Belgium.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, Non-U.S. Gov't