title: Synthesis of 4-(3-biaryl)quinoline sulfones as potent liver X receptor agonists.
abstract: A series of 4-(3-biaryl)quinolines with sulfone substituents on the terminal aryl ring (8) was prepared as potential LXR agonists. High affinity LXRbeta ligands with generally modest binding selectivity over LXRalpha and excellent agonist potency in LXR functional assays were identified. Many compounds had LXRbeta binding IC(50) values <10 nM while the most potent had EC(50) values <1.0 nM in an ABCA1 mRNA induction assay in J774 mouse cells with efficacy comparable to T0901317. Sulfone 8a was further evaluated in LDL (-/-) mice and shown to reduce atherosclerotic lesion progression.
authors.affiliation: Chemical Sciences, Wyeth Pharmaceuticals, 500 Arcola Road, Collegeville, PA 19426, USA. JWUllrich@comcast.net
authors.forename: John W
authors.initials: JW
authors.lastname: Ullrich
authors.forename: Robert
authors.initials: R
authors.lastname: Morris
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Bernotas
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Travins
authors.forename: James
authors.initials: J
authors.lastname: Jetter
authors.forename: Rayomand
authors.initials: R
authors.lastname: Unwalla
authors.forename: Elaine
authors.initials: E
authors.lastname: Quinet
authors.forename: Ponnal
authors.initials: P
authors.lastname: Nambi
authors.forename: Irene
authors.initials: I
authors.lastname: Feingold
authors.forename: Christine
authors.initials: C
authors.lastname: Huselton
authors.forename: Christofer
authors.initials: C
authors.lastname: Enroth
authors.forename: Anna
authors.initials: A
authors.lastname: Wilhelmsson
authors.forename: Annika
authors.initials: A
authors.lastname: Goos-Nilsson
authors.forename: Jay
authors.initials: J
authors.lastname: Wrobel
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy; D001665:Binding Sites; D002460:Cell Line; D003198:Computer Simulation; D006801:Humans; D008077:Lipoproteins, LDL / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000071518:Liver X Receptors; D051379:Mice; D018345:Mice, Knockout; D008861:Microsomes / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000819:agonists* / Q000378:metabolism; D011804:Quinolines / Q000737:chemistry*; D051381:Rats; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use
chemical_list: D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; C000605215:Nr1h3 protein, rat; D057093:Orphan Nuclear Receptors; D011804:Quinolines; D013450:Sulfones; C037219:quinoline