Linked Life Data

20888243

Source:http://linkedlifedata.com/resource/pubmed/id/20888243

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
21
pubmed:dateCreated
2010-10-18
pubmed:abstractText
With the increasing realization that modulating a multiplicity of targets can be an asset in the treatment of multifactorial disorders, we hereby report the synthesis and evaluation of the first compounds in which antioxidant, anti-inflammatory as well as squalene synthase (SQS) inhibitory activities are combined by design, in a series of simple molecules, extending their potential range of activities against the multifactorial disease of atherosclerosis. The activity of the initially synthesized antihyperlipidemic morpholine derivatives (1-6), in which we combined several pharmacophore moieties, was evaluated in vitro (antioxidant, inhibition of SQS and lipoxygenase) and in vivo (anti-dyslipidemic and anti-inflammatory effect). We further compared the in vitro SQS inhibitory action of these derivatives with theoretically derived molecular interactions by performing an in silico docking study using the X-ray crystal structure of human SQS. Based on low energy preferred binding modes, we designed potentially more potent SQS ligands. We proceeded with synthesizing and evaluating these new structures (7-12) in vitro and in vivo, to show that the new derivatives were significantly more active than formerly developed congeners, both as SQS inhibitors (20-70-fold increase in activity) and antioxidants (4-30-fold increase in activity). A significant correlation between experimental activity [Log(1/IC(50))] and the corresponding binding free energy (?G(b)) of the docked compounds was shown. These results, taken together, show a promising alternative and novel approach for the design and development of multifunctional antiatherosclerosis agents.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
1464-3391
pubmed:author
pubmed:copyrightInfo
Copyright © 2010 Elsevier Ltd. All rights reserved.
pubmed:issnType
Electronic
pubmed:day
1
pubmed:volume
18
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
7402-12
pubmed:meshHeading
pubmed:year
2010
pubmed:articleTitle
Design of more potent squalene synthase inhibitors with multiple activities.
pubmed:affiliation
Department of Pharmaceutical Chemistry, School of Pharmacy, University of Athens, 15771 Athens, Greece. angeliki@pharm.uoa.gr
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't