Document Detail


Discovery of phenyl acetic acid substituted quinolines as novel liver X receptor agonists for the treatment of atherosclerosis.
MedLine Citation:
PMID:  17034119     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A structure-based approach was used to optimize our new class of quinoline LXR modulators leading to phenyl acetic acid substituted quinolines 15 and 16. Both compounds displayed good binding affinity for LXRbeta and LXRalpha and were potent activators in LBD transactivation assays. The compounds also increased expression of ABCA1 and stimulated cholesterol efflux in THP-1 cells. Quinoline 16 showed good oral bioavailability and in vivo efficacy in a LDLr knockout mouse model for lesions.
Authors:
Baihua Hu; Michael Collini; Rayomand Unwalla; Christopher Miller; Robert Singhaus; Elaine Quinet; Dawn Savio; Anita Halpern; Michael Basso; James Keith; Valerie Clerin; Liang Chen; Christine Resmini; Qiang-Yuan Liu; Irene Feingold; Christine Huselton; Farooq Azam; Mathias Farnegardh; Cristofer Enroth; Tomas Bonn; Annika Goos-Nilsson; Anna Wilhelmsson; Ponnal Nambi; Jay Wrobel
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Publication Detail:
Type:  In Vitro; Journal Article    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  49     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2006 Oct 
Date Detail:
Created Date:  2006-10-12     Completed Date:  2006-12-04     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  6151-4     Citation Subset:  IM    
Affiliation:
Chemical and Screening Science, Cardiovascular and Metabolic Disease, and Bio Transformation and Disposition, Wyeth Research, 500 Arcola Road, Collegeville, Pennsylvania 19426, USA. hub@wueth.com
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MeSH Terms
Descriptor/Qualifier:
ATP-Binding Cassette Transporters / biosynthesis
Animals
Anticholesteremic Agents / chemical synthesis*,  chemistry,  pharmacology
Atherosclerosis / drug therapy*
Binding Sites
Biological Availability
Cell Line
Cholesterol / metabolism
DNA-Binding Proteins / agonists*,  genetics
Drug Stability
Female
Humans
Ligands
Male
Mice
Mice, Inbred C57BL
Microsomes, Liver / metabolism
Models, Molecular
Molecular Structure
Orphan Nuclear Receptors
Phenylacetates / chemical synthesis*,  chemistry,  pharmacology
Protein Structure, Tertiary
Quinolines / chemical synthesis*,  chemistry,  pharmacology
Receptors, Cytoplasmic and Nuclear / agonists*,  genetics
Structure-Activity Relationship
Transcriptional Activation
Chemical
Reg. No./Substance:
0/ATP binding cassette transporter 1; 0/ATP-Binding Cassette Transporters; 0/Anticholesteremic Agents; 0/DNA-Binding Proteins; 0/Ligands; 0/Orphan Nuclear Receptors; 0/Phenylacetates; 0/Quinolines; 0/Receptors, Cytoplasmic and Nuclear; 0/liver X receptor; 103-82-2/phenylacetic acid; 57-88-5/Cholesterol

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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