Linked Life Data

20807504

Source:http://linkedlifedata.com/resource/pubmed/id/20807504

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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2010-10-4
pubmed:abstractText
The development of antagonists to the ?4 integrin family of cell adhesion molecules has been an active area of pharmaceutical research to treat inflammatory and autoimmune diseases. Presently being tested in human clinical trials are compounds selective for ?4?1 (VLA-4) as well as several dual antagonists that inhibit both ?4?1 and ?4?7. The value of a dual versus a selective small molecule antagonist as well as the consequences of inhibiting different affinity states of the ?4 integrins have been debated in the literature. Here, we characterize TBC3486, a N,N-disubstituted amide, which represents a unique structural class of non-peptidic, small molecule VLA-4 antagonists. Using a variety of adhesion assay formats as well as flow cytometry experiments using mAbs specific for certain activation-dependent integrin epitopes we demonstrate that TBC3486 preferentially targets the high affinity conformation of ?4?1 and behaves as a ligand mimetic. The antagonist is capable of blocking integrin-dependent T-cell co-activation in vitro as well as proves to be efficacious in vivo at low doses in two animal models of allergic inflammation. These data suggest that a small molecule ?4 integrin antagonist selective for ?4?1 over ?4?7 and, specifically, selective for the high affinity conformation of ?4?1 may prove to be an effective therapy for multiple inflammatory diseases in humans.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
1090-2104
pubmed:author
pubmed:copyrightInfo
Copyright © 2010 Elsevier Inc. All rights reserved.
pubmed:issnType
Electronic
pubmed:day
1
pubmed:volume
400
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
619-24
pubmed:meshHeading
pubmed:year
2010
pubmed:articleTitle
Potent in vivo suppression of inflammation by selectively targeting the high affinity conformation of integrin ?4?1.
pubmed:affiliation
Department of Drug Discovery, Biological Sciences, Encysive Pharmaceuticals, Inc., Houston, TX, USA. pvanderslice@heart.thi.tmc.edu
pubmed:publicationType
Journal Article