Linked Life Data

16611081

Source:http://linkedlifedata.com/resource/pubmed/id/16611081

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
9
pubmed:dateCreated
2006-4-13
pubmed:abstractText
The enterohepatic circulation of bile acids is a major regulator of serum cholesterol homeostasis. After biosynthesis from cholesterol in the liver, bile acids are secreted with bile into the lumen of the small intestine to aid in the digestion and absorption of fat and fat-soluble vitamins. The bile acids are nearly quantitatively reabsorbed in the terminal ileum by a Na+-dependent transport system (IBAT) and are transported with portal blood to the liver and taken up by a second Na+-/bile acid cotransporter (LBAT) to be resecreted into bile. In the liver bile acids inhibit the rate-limiting enzyme for the conversion of cholesterol into bile acid: cholesterol-7alpha-hydroxylase; interruption of the enterohepatic circulation of bile acids withdraws this feedback inhibition and leads to an upregulation of hepatic LDL-receptors with a concomitant decrease of serum LDL-levels. Specific inhibitors of the ileal bile acid transporter belonging to different chemotypes have been developed in recent years for this purpose, some now entering clinical stage. To exert a profound systemic effect these compounds do not need to be available systemically but can act from the luminal side of the small intestine, which offers the advantage to avoid the well-known adverse side effects of other hypolipidemic drugs like statins due to metabolism and drug-drug interactions in the liver. This implies several aspects in compound optimization and drug development quite different from standard procedures, for example the concept of low absorption drugs was established to avoid systemic side effects. The review article covers the mechanistic and therapeutic principles of the approach and presents an overview on the molecular target, the discovery of specific inhibitors and respective optimization strategies.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:issn
0929-8673
pubmed:author
pubmed:issnType
Print
pubmed:volume
13
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
997-1016
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed:year
2006
pubmed:articleTitle
Bile acid reabsorption inhibitors (BARI): novel hypolipidemic drugs.
pubmed:affiliation
TD Metabolism, Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, Building G 879, 65926 Frankfurt am Main, Germany. Werner.Kramer@sanofi-aventis.com
pubmed:publicationType
Journal Article, Review