title: Indazole-based liver X receptor (LXR) modulators with maintained atherosclerotic lesion reduction activity but diminished stimulation of hepatic triglyceride synthesis.
abstract: A series of substituted 2-benzyl-3-aryl-7-trifluoromethylindazoles were prepared as LXR modulators. These compounds were partial agonists in transactivation assays when compared to 1 (T0901317) and were slightly weaker with respect to potency and efficacy on LXRalpha than on LXRbeta. Lead compounds in this series 12 (WAY-252623) and 13 (WAY-214950) showed less lipid accumulation in HepG2 cells than potent full agonists 1 and 3 (WAY-254011) but were comparable in efficacy to 1 and 3 with respect to cholesterol efflux in THP-1 foam cells, albeit weaker in potency. Compound 13 reduced aortic lesion area in LDLR knockout mice equivalently to 3 or positive control 2 (GW3965). In a 7-day hamster model, compound 13 showed a lesser propensity for plasma TG elevation than 3, when the compounds were compared at doses in which they elevated ABCA1 and ABCG1 gene expression in duodenum and liver at equal levels. In contrast to results previously published for 2, the lack of TG effect of 13 correlated with its inability to increase liver fatty acid synthase (FAS) gene expression, which was up-regulated 4-fold by 3. These results suggest indazoles such as 13 may have an improved profile for potential use as a therapeutic agent.
authors.affiliation: Chemical and Screening Sciences, Wyeth Pharmaceuticals, 500 Arcola Road, Collegeville, Pennsylvania 19426, USA. wrobelj@wyeth.com
authors.forename: Jay
authors.initials: J
authors.lastname: Wrobel
authors.forename: Robert
authors.initials: R
authors.lastname: Steffan
authors.forename: S Marc
authors.initials: SM
authors.lastname: Bowen
authors.forename: Ronald
authors.initials: R
authors.lastname: Magolda
authors.forename: Edward
authors.initials: E
authors.lastname: Matelan
authors.forename: Rayomand
authors.initials: R
authors.lastname: Unwalla
authors.forename: Michael
authors.initials: M
authors.lastname: Basso
authors.forename: Valerie
authors.initials: V
authors.lastname: Clerin
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Gardell
authors.forename: Ponnal
authors.initials: P
authors.lastname: Nambi
authors.forename: Elaine
authors.initials: E
authors.lastname: Quinet
authors.forename: Jason I
authors.initials: JI
authors.lastname: Reminick
authors.forename: George P
authors.initials: GP
authors.lastname: Vlasuk
authors.forename: Shuguang
authors.initials: S
authors.lastname: Wang
authors.forename: Irene
authors.initials: I
authors.lastname: Feingold
authors.forename: Christine
authors.initials: C
authors.lastname: Huselton
authors.forename: Tomas
authors.initials: T
authors.lastname: Bonn
authors.forename: Mathias
authors.initials: M
authors.lastname: Farnegardh
authors.forename: Tomas
authors.initials: T
authors.lastname: Hansson
authors.forename: Annika Goos
authors.initials: AG
authors.lastname: Nilsson
authors.forename: Anna
authors.initials: A
authors.lastname: Wilhelmsson
authors.forename: Edouard
authors.initials: E
authors.lastname: Zamaratski
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Evans
mesh_terms: D000818:Animals; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D006224:Cricetinae; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D008958:Models, Molecular; D015394:Molecular Structure; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D014280:Triglycerides / Q000096:biosynthesis* / Q000097:blood
chemical_list: D004268:DNA-Binding Proteins; D007191:Indazoles; D008024:Ligands; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D014280:Triglycerides