Indazole-Based Liver X Receptor (LXR) Modulators with Maintained Atherosclerotic Lesion Reduction Activity but Diminished Stimulation of Hepatic Triglyceride Synthesis

• Published in: Journal of medicinal chemistry Vol. 51; no. 22; pp. 7161 - 7168
• Main Authors: Wrobel, Jay, Steffan, Robert, Bowen, S. Marc, Magolda, Ronald, Matelan, Edward, Unwalla, Rayomand, Basso, Michael, Clerin, Valerie, Gardell, Stephen J, Nambi, Ponnal, Quinet, Elaine, Reminick, Jason I, Vlasuk, George P, Wang, Shuguang, Feingold, Irene, Huselton, Christine, Bonn, Tomas, Farnegardh, Mathias, Hansson, Tomas, Nilsson, Annika Goos, Wilhelmsson, Anna, Zamaratski, Edouard, Evans, Mark J
• Format: Journal Article
• Language: English
• Published: Columbus, OH American Chemical Society 27-11-2008
• Subjects: Animals; Arteriosclerosis - drug therapy; Arteriosclerosis - metabolism; Biological and medical sciences; Cell Differentiation - drug effects; Cell Line; Cricetinae; Crystallography, X-Ray; DNA-Binding Proteins - agonists; DNA-Binding Proteins - metabolism; General and cellular metabolism. Vitamins; Humans; Hydrogen Bonding; Indazoles - chemical synthesis; Indazoles - chemistry; Indazoles - pharmacology; Ligands; Liver - drug effects; Liver - metabolism; Liver X Receptors; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Animal; Models, Molecular; Molecular Structure; Orphan Nuclear Receptors; Pharmacology. Drug treatments; Receptors, Cytoplasmic and Nuclear - agonists; Receptors, Cytoplasmic and Nuclear - metabolism; Recombinant Proteins - drug effects; Recombinant Proteins - metabolism; Structure-Activity Relationship; Triglycerides - biosynthesis; Triglycerides - blood; Partial agonist; Nuclear receptor; Intravenous administration; Nitrogen heterocycle; Liver; Modeling; Signal transduction; Anti-astherosclerotic; Hepatocyte; Structure activity relation; Molecular model; Bicyclic compound; Aromatic compound; Chemical synthesis; Tumor cell; Human; Ligand binding; Rodentia; Benzene derivatives; Oral administration; Triglyceride; Indazole derivatives; In vitro; In vivo; Vertebrata; Mammalia; Cell line; Mouse; Animal; Liver X receptor; Affinity; Fluorine Organic compounds; Pharmacokinetics; Hamster; Hormonal receptor
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm800799q

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 LXRα than on LXRβ. 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.