title: Discovery of phenyl acetic acid substituted quinolines as novel liver X receptor agonists for the treatment of atherosclerosis.
abstract: 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.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
authors.forename: Baihua
authors.initials: B
authors.lastname: Hu
authors.forename: Michael
authors.initials: M
authors.lastname: Collini
authors.forename: Rayomand
authors.initials: R
authors.lastname: Unwalla
authors.forename: Christopher
authors.initials: C
authors.lastname: Miller
authors.forename: Robert
authors.initials: R
authors.lastname: Singhaus
authors.forename: Elaine
authors.initials: E
authors.lastname: Quinet
authors.forename: Dawn
authors.initials: D
authors.lastname: Savio
authors.forename: Anita
authors.initials: A
authors.lastname: Halpern
authors.forename: Michael
authors.initials: M
authors.lastname: Basso
authors.forename: James
authors.initials: J
authors.lastname: Keith
authors.forename: Valerie
authors.initials: V
authors.lastname: Clerin
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.forename: Christine
authors.initials: C
authors.lastname: Resmini
authors.forename: Qiang-Yuan
authors.initials: QY
authors.lastname: Liu
authors.forename: Irene
authors.initials: I
authors.lastname: Feingold
authors.forename: Christine
authors.initials: C
authors.lastname: Huselton
authors.forename: Farooq
authors.initials: F
authors.lastname: Azam
authors.forename: Mathias
authors.initials: M
authors.lastname: Farnegardh
authors.forename: Cristofer
authors.initials: C
authors.lastname: Enroth
authors.forename: Tomas
authors.initials: T
authors.lastname: Bonn
authors.forename: Annika
authors.initials: A
authors.lastname: Goos-Nilsson
authors.forename: Anna
authors.initials: A
authors.lastname: Wilhelmsson
authors.forename: Ponnal
authors.initials: P
authors.lastname: Nambi
authors.forename: Jay
authors.initials: J
authors.lastname: Wrobel
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis; D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D050197:Atherosclerosis / Q000188:drug therapy*; D001665:Binding Sites; D001682:Biological Availability; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000235:genetics; D004355:Drug Stability; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D057093:Orphan Nuclear Receptors; D010648:Phenylacetates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000924:Anticholesteremic Agents; D004268:DNA-Binding Proteins; D008024:Ligands; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D010648:Phenylacetates; D011804:Quinolines; D018160:Receptors, Cytoplasmic and Nuclear; D002784:Cholesterol; C025136:phenylacetic acid