TO901317

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TO901317
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Executive Summary Information

Compound TO901317 (N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide)
Toxicities Steatosis
Mechanisms Dual liver X receptor (LXR) and pregnane X receptor (PXR) agonist.
Comments TO901317 is a standard for induction of steatosis via ligand-receptor mediated increases in of fatty acid synthesis, as opposed to inhibition of fatty acid oxidation by chemically reactive compounds.
Feedback Contact Gold Compound Working Group (GCWG)
TO901317
TO901317.png


Identifiers
Leadscope Id LS-185184
CAS 293754-55-9
Pathway DBs
Assay DBs
PubChem CID 447912
Omics DBs
Properties
ToxCast Accepted no
Toxic Effect Steatosis
ToxBank Accepted yes
Approved on 2011-06-28


In Vivo Data ? Compound Assessment
Adverse Events ? TO901317 causes steatosis and serum hypertriglyceridemia associated with lipogenesis in mouse models.

References:

-Grefhorst, A., Elzinga, B. M., Voshol, P. J., Plosch, T., Kok, T., Bloks, V. W., van der Sluijs, F. H., Havekes, L. M., Romijn, J. A., Verkade, H. J., and Kuipers, F., “Stimulation of lipogenesis by pharmacological activation of the liver X receptor (LXR) leads to production of large, triglyceride-rich VLDL particles”, J Biol Chem. 277(37), 34182-90, (2002)
-Schultz, J. R., Tu, H., Luk, A., Repa, J. J., Medina, J. C., Li, L.,

Schwendner, S., Wang, S., Thoolen, M., Mangelsdorf, D. J., Lustig, K. D., and Shan, B., “

Role of LXRs in control of lipogenesis”, Genes Dev.,14, 2831-2838, (2000)
-Jeffrey W. Chisholm,Jenny Hong, Scott A. Mills, and Richard M. Lawn, “The LXR ligand TO901317 induces severe lipogenesis in the db/db diabetic mouse”, J. Lipid Res. (2003) 44:2039–2048.
Toxicity Mechanisms ? TO901317 is an agonist for the LXR-α and LXR-β nuclear hormone receptors, and there is strong evidence that TO901317-induced hepatic steatosis is linked to activation of these receptors (Schultz, et al., 2000). LXR-α expression is restricted to liver, kidney, intestine, fat tissue, macrophages, lung, and spleen and is highest in liver, hence the name liver X receptor α (LXR-α). LXR-β is expressed in almost all tissues and organs, hence the early name UR (ubiquitous receptor). The different patterns of expression suggest that LXR-α and LXR-β have different roles in regulating physiological function but the extent of the differentiation is not yet clear.

References:

-Schultz, J. R., Tu, H., Luk, A., Repa, J. J., Medina, J. C., Li, L., Schwendner, S., Wang, S., Thoolen, M., Mangelsdorf, D. J., Lustig, K. D., and Shan, B., “Role of LXRs in control of lipogenesis”, Genes Dev.,14, 2831-2838, (2000)

LXR receptors have been proposed as targets for atherosclerosis therapy because agonists such as TO901317 promote the reverse transport of cholesterol from peripheral tissues to HDL particles in the circulation and subsequent uptake of the cholesterol in the liver followed by excretion of the cholesterol to the bile. Desirable effects of TO901317 on peripheral cholesterol are accompanied by increased fatty acid synthesis leading to steatosis in the liver and hypertriglyceridemia, however, so that the therapeutic potential of these agonists is limited (Repa, et al., 2000; Miao, et al., 2004; Oosterveer et al., 2010).


References:

-Repa JJ, Turley SD, Lobaccaro JA, Medina J, Li L, Lustig K, Shan B, Heyman RA, Dietschy JM, Mangelsdorf DJ, “Regulation of Absorption and ABC1-Mediated Efflux of Cholesterol by RXR Heterodimers”, Science, 289, 1524-1529 (2000)
-Maaike H. Oosterveer, Aldo Grefhorst, Albert K. Groen, Folkert Kuipers, “The liver X receptor: Control of cellular lipid homeostasis and beyond Implications for drug design”, Progress in Lipid Research 49 (2010) 343–352.

Attempts to identify compounds with increased therapeutic index for anti-atherosclerotic activity vs. steatosis identified GW3965 as an LXR agonist without steatotic activity (Collins, et al., 2002; Miao, et al., 2004). It was subsequently shown that TO901317, but not GW3965, is a PXR agonist with potency vs. PXR comparable to that for the LXR receptors (Mitro, et al., 2007). It appears, therefore, that LXR agonism is not sufficient to induce steatosis, and in the absence of an alternative explanation, it is concluded that dual LXR-PXR agonism is required. The effect of PXR agonism on steatosis is proposed, at least in part, to be the result of up-regulation of CD36, a high affinity fatty acid transporter.


References:

-Jon L. Collins, Adam M. Fivush, Michael A. Watson, Cristin M. Galardi, Michael C. Lewis, Linda B. Moore, Derek J. Parks, Joan G. Wilson, Tim K. Tippin, Jane G. Binz, Kelli D. Plunket, Daniel G. Morgan, Elizabeth J. Beaudet, Karl D. Whitney, Steven A. Kliewer, and Timothy M. Willson, “Identification of a Nonsteroidal Liver X Receptor Agonist through Parallel Array Synthesis of Tertiary Amines”, J. Med. Chem. (2002) 45, 1963-1966
-Bowman Miao, Susan Zondlo, Sandy Gibbs, Debra Cromley, Vinayak P. Hosagrahara, Todd G. Kirchgessner, Jeffrey Billheimer, and Ranjan Mukherjee , “Raising HDL cholesterol without inducing hepatic steatosis and hypertriglyceridemia by a selective LXR modulator”, J. Lipid Res. (2004) 45:1410–1417
-Mitro N, Mak PA, Vargas L, Godio C, Hampton E, Molteni V, Kreusch A, and Saez E, “TO901317 is a potent PXR ligand: Implications for the biology ascribed to LXR”, FEBS Letters, 581, 1721–1726, (2007)

The above results imply that uptake of exogenous fatty acids is required for TO901317-induced steatosis, and there is evidence that TO901317 induces synthesis and release of free fatty acids by adipocytes (Oosterveer, et al., 2010). Thus CD36-mediated uptake of these fatty acids (He, et al., 2011), perhaps as an additional burden to endogenously synthesized fatty acids, appears to be necessary to push the liver to steatosis. Interestingly, GW3965 is distinguishable from TO901317 in adipocytes as well as hepatocytes. GW3965 has been reported to induce fatty acid oxidation in adipocytes rather than release of free fatty acids, as is seen for TO901317 (Oosterveer, et al., 2010).

References:

-Maaike H. Oosterveer, Aldo Grefhorst, Albert K. Groen, Folkert Kuipers, “The liver X receptor: Control of cellular lipid homeostasis and beyond Implications for drug design”, Progress in Lipid Research 49 (2010) 343–352.
-Jinhan He, Jung Hoon Lee, Maria Febbraio and Wen Xie, “The emerging roles of fatty acid translocase/CD36 and the aryl hydrocarbon receptor in fatty liver disease”, Experimental Biology and Medicine 2011; 236: 1116–1121.

High-throughput screening of environmental chemicals for binding to nuclear hormone receptors gave a hit rate of 7% for LXR, and 70% of these were PXR ligands with binding affinities within 1 log of the LXR affinity (Martin, et al., 2010). Although these hit rates are dependent on the specific compounds screened, they indicate a reasonably high probability of finding dual LXR-PXR ligands.

References:

-Matthew T. Martin, David J. Dix, Richard S. Judson, Robert J. Kavlock, David M. Reif, Ann M. Richard, Daniel M. Rotroff, Sergei Romanov, Alexander Medvedev, Natalia Poltoratskaya, Maria Gambarian, Matt Moeser, Sergei S. Makarov, and Keith A. Houck, “Impact of Environmental Chemicals on Key Transcription Regulators and Correlation to Toxicity End Points within EPA’s ToxCast Program”, Chem. Res. Toxicol. 2010, 23, 578–590.
Therapeutic Target ? Suggested possible therapeutic targets related to the LXR activation include atherosclerosis, dyslipidemia, diabetes, Alzheimer's disease, arthritis, skin diseases and regulation of cell cycle in human colon (colon cancer treatment). However TO901317 is not an approved chemical for medical use mainly due to its steatotic action.

References:

-Tomas Jakobsson, Eckardt Treuter, Jan-Åke Gustafsson and Knut R. Steffensen, “Liver X receptor biology and pharmacology: new pathways, challenges and opportunities”, Trends in Pharmacological Sciences, 33:394-404, (2012)
-Edwards P.A., et al, LXRs; Oxysterol-activated nuclear receptors that regulate genes controlling lipid homeostasis, (Oxidized Lipids as Potential Mediators of Atherosclerosis), Vascular Pharmacology, 38 (No 4), 249–256, 2002
-Maaike H. Oosterveer, Aldo Grefhorst, Albert K. Groen, Folkert Kuipers, “The liver X receptor: Control of cellular lipid homeostasis and beyond Implications for drug design”, Progress in Lipid Research 49 (2010) 343–352.
-Chuu CP, Kokontis JM,Hiipakka RA, Liao S (2007). "Modulation of liver X receptor signaling as novel therapy for prostate cancer". J. Biomed. Sci. 14: 543–53.



PubMed references

The following resource link will perform a PubMed query for the terms "TO901317" and "steatosis".
TO901317 Search

References


PK-ADME ? Compound Assessment
PK parameters ? The Cmax of TO901317 attained in mouse plasma is approximately 1.4 ug/ml for a dose of 10 mg/kg and 0.2 ug/ml for a dose of 2 mg/kg. The half-life in blood was around 5 h (Peng et al 2008).

References:

-Peng D, Hiipakka RA, Dai Q, Guo J, Reardon CA, Getz GS, and Liao S, “Antiatherosclerotic Effects of a Novel Synthetic Tissue-Selective Steroidal Liver X Receptor Agonist in Low-Density Lipoprotein Receptor-Deficient Mice”, JPET, 327, 332–342, (2008)
Therapeutic window ? Not applicable
Metabolically activated ? No

Omics and IC50 Data ? Compound Assessment
Gene expression profiles known. ? Upon TO901317 induced activation both LXR isoforms form obligate heterodimers with the retinoid X receptor (RXR) and regulate gene expression through binding to LXR response elements (LXREs) in the promoter regions of the target genes (Fig. 1, Baranowski 2008). LXRE consists of two idealized hexanucleotide sequences (AGGTCA) separated by four bases (DR-4 element).
LXR-RXR Binding
Figure 1. Binding of the LXR-RXR heterodimers in the LXREs

Target genes of LXRs after binding of the TO901317 are involved in cholesterol, glucose and lipid metabolism regulation (Table 1.)

TissueGeneFull NameReferenceFunction
Liver ABC A1 ATP Binding Cassette transporter isoforms A1 Costet et al 2000, Kennedy et al 2001, Repa et al 2000, Mitro et al 2007 Efflux of phospholipids and/or cholesterol
ABC G5, G8 ATP Binding Cassette transporter isoforms G5 and G8 Mitro et al 2007 Efflux of cholesterol and phytosterols
CYP 7A1 Cytochrome P450 isoform 7A1-cholesterol 7a=hydroxylase Lehmann et all 1997, Mitro et all 2007 Rate-limiting enzyme in the classical bile acid biosynthetic pathway, clearance of cholesterol
ACC* Acetyl-CoA Carboxylase Schultz et al 2000, Peng et al 2008 Provides the malonyl-CoA substrate for the biosynthesis of fatty acids
FAS* Fatty Acid Synthase Shultz et al 2000, Mitro et al 2007 Fatty acids synthesis
LPL Lipoprotein Lipase Peng et al 2008 Triglicerides metabolism
PLTP Phospholipid Transfer Protein Peng et al 2008 Transfer of phospholipids from triglyceride-rich lipoproteins to HDL, cholesterol metabolism
LXRa Liver X Receptor a Laffitte et al 2001, Whitney et al 2001 Transcriptional control of lipid homeostasis
FA/CD 36* Fatty Acid Transfer Protein Mitro et al 2007 Fatty acids transport
SCD-1 stearol-Coenzyme A desaturase 1 Schultz et al 2000, Mitro et al 2007 Catalyzes a rate-limiting step in the synthesis of unsaturated fatty acids
SREBP-1c Sterol Response Element Binding Protein 1c Schultz et al 2000, Mitro et al 2007 Cholesterol biosynthesis and fatty acid uptake and biosynthesis
ChREBP Carbohydrate Response Element Binding Protein Cha and Repa 2007, Denechaud et al 2008 Glucose-activated transcription factor
CETP Cholesterylester Transfer Protein Luo and Tall 2000 Redistribution of cholesteryl esters, triglycerides, and to a lesser extent, phospholipids between plasma proteins
CPT-1 Carnitin palmytoyltransferase 1 Schultz et al 2000 Transport of long-chain fatty acids
ACBP acyl-CoA binding protein Schultz et al 2000 Intracellular carrier of acytl-CoA esters
- Acyl glycerol-3-phosphate acylotranferase Schultz et al 2000 Glycerolipid metabolism, glycerophospholipid metabolism, and ether lipid metabolism.
FAAH FA amide hydrolase Schultz et al 2000 Principal catabolic enzyme for a class of bioactive lipids called the fatty acid amides
ACP Acyl carrier protein Schultz et al 2000 Both fatty acid and polyketide biosynthesis
FABPs FA binding and transport proteins Schultz et al 2000 FA binding and transport proteins
CLPS Colipase Schultz et al 2000 Protein co-enzyme required for optimal enzyme activity of pancreatic lipase
ECT Phospoethanolamine cytidylyltranferase Schultz et al 2000 Transferase
Small Intestine ATP A1, G1, G8 ATP Binding Cassette transporter isoforms Peng et al 2008 -
Peritoneal Macrophages ATP A1, G1, G5 ATP Binding Cassette transporter isoforms Peng et al 2008 -
ApoE Apolipoprotein E Laffitte et al 2001 Clearance of cholesterol
* Target gene for both LXR and PXR

References:

-Costet P., et al, Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor, J Biol Chem., 275(36), 28240-5, 2000
-Mitro N, Mak PA, Vargas L, Godio C, Hampton E, Molteni V, Kreusch A, and Saez E, “TO901317 is a potent PXR ligand: Implications for the biology ascribed to LXR”, FEBS Letters, 581, 1721–1726, (2007)
-Schultz, J. R., Tu, H., Luk, A., Repa, J. J., Medina, J. C., Li, L., Schwendner, S., Wang, S., Thoolen, M., Mangelsdorf, D. J., Lustig, K. D., and Shan, B., “Role of LXRs in control of lipogenesis”, Genes Dev.,14, 2831-2838, (2000)
-Kennedy MA, Venkateswaran A, Tarr PT, Xenarios I, Kudoh J, Shimizu N, Edwards PA, “Characterization of the human ABCG1 gene: liver X receptor activates an internal promoter that produces a novel transcript encoding an alternative form of the protein”, J Biol Chem., 276(42), 39438-47, (2001)
-Repa JJ, Turley SD, Lobaccaro JA, Medina J, Li L, Lustig K, Shan B, Heyman RA, Dietschy JM, Mangelsdorf DJ, “Regulation of Absorption and ABC1-Mediated Efflux of Cholesterol by RXR Heterodimers”, Science, 289, 1524-1529 (2000)
-Lehmann, J. M., S. A. Kliewer, L. B. Moore, T. A. Smith-Oliver, B. B. Oliver, J. L. Su, S. S. Sundseth, D. A. Winegar, D. E. Blanchard, T. A. Spencer, and T. M. Willson. (1997) “Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway”, J. Biol. Chem. 272: 3137–3140.
-Lehmann, J. M., S. A. Kliewer, L. B. Moore, T. A. Smith-Oliver, B. B. Oliver, J. L. Su, S. S. Sundseth, D. A. Winegar, D. E. Blanchard, T. A. Spencer, and T. M. Willson. (1997) “Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway”, J. Biol. Chem. 272: 3137–3140.
-Bryan A. Laffitte, Sean B. Joseph, Robert Walczak, Liming Pei, Damien C. Wilpitz, Jon L. Collins, and Peter Tontonoz, “Autoregulation of the human liver X receptor alpha promoter”, Mol. Cell. Biol., 21, 7558-7568, (2001)
-Cha Ji-Young and Repa J.J., “The Liver X-receptor (LXR) and Hepatic Lipogenesis”, The Journal of Biological Chemistry, 282:743-751, (2007)
-Pierre-Damien Denechaud, Pascale Bossard, Jean-Marc A. Lobaccaro, Lesley Millatt, Bart Staels, Jean Girard, and Catherine Postic, “ChREBP, but not LXRs, is required for the induction of glucose-regulated genes in mouse liver”, J Clin Invest, 118. 956-964, 2008
-Luo Y. and Tall AR., “Sterol upregulation of human CETP expression in vitro and in transgenic mice by an LXR element”, J Clin Invest., 105:513-20, (2000)
-Karl D. Whitney, Michael A. Watson, Bryan Goodwin, Cristin M. Galardi, Jodi M. Maglich, Joan G. Wilson, Timothy M. Willson, Jon L. Collins and Steven A. Kliewer, “Liver X receptor (LXR) regulation of the LXR alpha gene in human macrophages”,J. Biol. Chem. 276, 43509-43515, (2001)

In addition, Peet et al studied the genes expression in relation to high cholesterol diet at in LXR null mice (Peet et al 1998).

References:

-Daniel J Peet, Stephen D Turley, Wenzhen Ma, Bethany A Janowski, Jean-Marc A Lobaccaro, Robert E Hammer and David J Mangelsdorf, “Cholesterol and Bile Acid Metabolism Are Impaired in Mice Lacking the Nuclear Oxysterol Receptor LXRa in mammals”, Cell, 93, 693–704, 1998

In the study of Schultz et al (HepG2 and mice) inhibition of gene expression was indicated for the SQS, HMG and CoA S while apoAI, apoIII, apoD, apoE, MTP, NaTCP, SR-BI, apoCIII and DGAT remained unaffected. In the same study it is also mentioned that LXR-β has been seen to up-regulate cholesterol-associated genes in vitro but no in vivo in mice.


References:

-Schultz, J. R., Tu, H., Luk, A., Repa, J. J., Medina, J. C., Li, L., Schwendner, S., Wang, S., Thoolen, M., Mangelsdorf, D. J., Lustig, K. D., and Shan, B., “Role of LXRs in control of lipogenesis”, Genes Dev.,14, 2831-2838, (2000)

TO901317 also induced the classical PXR target CYP3A4 as well as other PXR regulated genes such as CYP3A11, GST4a and CYP2B10 in HepG2 cells (Mitro et al 2007).


References:

-Mitro N, Mak PA, Vargas L, Godio C, Hampton E, Molteni V, Kreusch A, and Saez E, “TO901317 is a potent PXR ligand: Implications for the biology ascribed to LXR”, FEBS Letters, 581, 1721–1726, (2007)

In the study of Kumar et al it was reported that TO901317 is binding to ROR α and γ inhibiting the G6Pase gene expression in HepG2 (Kumar et al 2010).

References:

-Kumar N, Solt LA, Conkright JJ, Wang Y, Istrate MA, Busby SA, Garcia-Ordonez RD, Burris TP, Griffin PR, “The Benzenesulfoamide TO901317 [N-(2,2,2-Trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide] Is a Novel Retinoic Acid Receptor-Related Orphan Receptor-_/_ Inverse Agonist”, Mol Pharmacol 77, 228–236 (2010)

Noteworthy is the fact that in many of the above mentioned studies like these of Repa et al 2000, Peet et al 1998 and Schultz et al 2000 LXRa -/- mice were used in order to examine if the genes expression is related specifically to the LXR.

Proteomics profiles known. ? A potential mechanism for how nuclear receptor LXR regulates cell cycle in human

colon cancer cells via EGFR/PI3K/Akt and ABCA1/SREBP-1/LDLR signaling (Ching-Yu,2012)

References:

-Ching-Yu L., et al, Application of high-throughput proteomics Micro-Western array in studying molecular mechanism of anticancer effect of liver X receptor agonists against human colon cancer cells, Cancer Research, 72(8), Supp.1, 2012
Metabonomics profiles known. ? No data
Fluxomics profiles known. ? No data
Epigenomics profiles known. ? No data
Observed IC50 for in vitro cellular efficacy. ? Not applicable
Observed IC50 for in vitro cellular toxicity studies. ? Cellular EC50’s for receptor agonism: potent modulator of LXR-α, LRXR-β, and PXR. Weaker binding to FXR and ROR indicates that in vitro studies should be conducted at 1 uM or lower to maximize selectivity.
LXR-αKd = 7 nM agonist (Schultz et al., 2000)
LXR-βKd = 22 nM agonist (Schultz et al., 2000)
PXREC50 = 23 nM agonist (Mitro et al., 2007)
FXREC50 = 5 µM agonist (Repa et al., 2000, Houck, 2004)
RORIC50 = 2 μM antagonist(Kumar et al., 2010)

References:

-Repa JJ, Turley SD, Lobaccaro JA, Medina J, Li L, Lustig K, Shan B, Heyman RA, Dietschy JM, Mangelsdorf DJ, “Regulation of Absorption and ABC1-Mediated Efflux of Cholesterol by RXR Heterodimers”, Science, 289, 1524-1529 (2000)
-Schultz, J. R., Tu, H., Luk, A., Repa, J. J., Medina, J. C., Li, L., Schwendner, S., Wang, S., Thoolen, M., Mangelsdorf, D. J., Lustig, K. D., and Shan, B., “Role of LXRs in control of lipogenesis”, Genes Dev.,14, 2831-2838, (2000)
-Keith A. Houck, Kristen M. Borchert, Christopher D. Hepler, JeVrey S. Thomas, Kelli S. Bramlett, Laura F. Michael, Thomas P. Burris, “TO901317 is a dual LXR/FXR agonist”, Molecular Genetics and Metabolism, 83, 184–187, 2004
-Kumar N, Solt LA, Conkright JJ, Wang Y, Istrate MA, Busby SA, Garcia-Ordonez RD, Burris TP, Griffin PR, “The Benzenesulfoamide TO901317 [N-(2,2,2-Trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide] Is a Novel Retinoic Acid Receptor-Related Orphan Receptor-_/_Inverse Agonist”, Mol Pharmacol 77, 228–236 (2010)
-Mitro N, Mak PA, Vargas L, Godio C, Hampton E, Molteni V, Kreusch A, and Saez E, “TO901317 is a potent PXR ligand: Implications for the biology ascribed to LXR”, FEBS Letters, 581, 1721–1726, (2007)

No available EC50 for triglyceride accumulation, available relevant data:


1.Goose primary hepatocytes: 72h, 0.01, 0.1, 1 and 10μM TO901317, Significant increase in the TG accumulation at the two higher doses (Han et al 2011).
2.Rat hepatoma cells McA-RH7777: 65h, 10 uM TO901317, 1.4 fold increase of TG mass (Grefhorst 2002)
3.Male C57BL/6J mice, 10mg/kg/d, 4 days, ca 8-fold increase in liver TG accumulation (Grefhorst 2002)
4.In vivo mice LOAEL 5mg/kg/bw for plasma TG and HDL increase (Schultz et al 2000)


References:

-Han C. C., et al, Effect of liver X receptor activation on the very low density lipoprotein secretion and messenger ribonucleic acid level of related genes in goose primary hepatocytes, Poultry Science, 90, 402–409, 2011
-Grefhorst, A., Elzinga, B. M., Voshol, P. J., Plosch, T., Kok, T., Bloks, V. W., van der Sluijs, F. H., Havekes, L. M., Romijn, J. A., Verkade, H. J., and Kuipers, F., “Stimulation of lipogenesis by pharmacological activation of the liver X receptor (LXR) leads to production of large, triglyceride-rich VLDL particles”, J Biol Chem. 277(37), 34182-90, (2002)
-Schultz, J. R., Tu, H., Luk, A., Repa, J. J., Medina, J. C., Li, L., Schwendner, S., Wang, S., Thoolen, M., Mangelsdorf, D. J., Lustig, K. D., and Shan, B., “Role of LXRs in control of lipogenesis”, Genes Dev.,14, 2831-2838, (2000)

Physical Properties ? Compound Assessment
Accepted and listed within the ToxCast/Tox21 program. ? No - Not included in ToxCast Phase I and II Chemicals List
Substance stability. ? It is not recommend storing the aqueous solutions for more than one day. Enzo Life Sciences

Stable for at least 1 year if stored as supplied, solid form, at -20°C or for 6 months at +4°C. Stable for at least 1 year if stored in dimethyl sulfoxide solution year at -20°C Cayman Chemicals

Soluble in buffer solution at 30 times the in vitro IC50 for toxicity. ? A stock solution may be made by dissolving the T09013l7 in an organic solvent purged with an inert gas. T090l317 is soluble in organic solvents such as ethanol, DMSO, and dimethyl formamide. The solubility of T090l3l7 in these solvents is approximately 50 mg/ml.

T0901317 is sparingly soluble in aqueous buffers. For maximum solubility in aqueous buffers, T09013l7 should be dissolved first in DMSO and then diluted with the aqueous buffer of choice. T09013l7 has a solubility of approximately 500 ug/ml (1 mM) in a 1:1 solution of DMSO:PBS (pl-I 7.2) using this method. It is not recommended storing the aqueous solution for more than one day. The formation of solutions could be also encouraged by rapid stirring, sonication or gentle warming (in a 45-60°C water bath). Cayman Chemicals
estimated intrinsic solubility : 9.1672E-05 mg/ml
estimated solubility in pure water at pH 7: 9.2587E-05 mg/ml
estimated solubility in water at pH 7.4: 9.4E-05 mg/ml
Calculations performed using ACD/PhysChem v 12.0

Solubility in DMSO 100 times buffer solubility. ? Soluble to 100 mM in DMSO and to 100 mM in ethanol

Tocris Bioscience (2373) Product Information

Vessel binding properties. ? Binding to plastic is likely but has not been quantitated
Vapor pressure. (Non-volatile) ? Non-volatile. Estimated vapor pressure (25°C): 1.42E-09 mmHg (Calculation performed using EPI Suite v4.10)


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  • 2. Ory D.S., NR Signaling in the control of Cholesterol Homeostasis: Have the orphans found a home?, Circ. Res., 95, 660-670, 2004
  • 3. Lund E.G., et al, Different roles of liver X receptor alpha and beta in lipid metabolism: effects of an alpha-selective and a dual agonist in mice deficient in each subtype, Biochem. Pharmacol., 71, 453–463, 2006
  • 4. Chu K., et al, Stearoyl-coenzyme A desaturase 1 deficiency protects against hypertriglyceridemia and increase plasma high-density lipoprotein cholesterol induced by liver X receptor activation, Mol Cell Biol, 26. 6786-6798, 2006
  • 5. Collins J.L., et al, Identification of a non-steroidal liver X receptor agonist through parallel array synthesis of tertiary amines, J Med Chem, 45, 1963-1966, 2002
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  • 8. Jamroz-Wiśniewska A., et al, Liver X receptors (LXRs). Part II: non-lipid effects, role in pathology, and therapeutic implications, Postepy. Hig. Med. Dosw., 61, 760-85, 2007
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  • 10. Kotokorpi P., et al. Physiological differences between human and rat primary hepatocytes in response to liver X receptor activation by 3-[3-[N-(2-chloro-3-trifluoromethylbenzyl)-(2,2-diphenylethyl)amino]propyl oxy]phenylacetic acid hydrochloride (GW3965). Mol Pharmacol 72, 947-955, 2007
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  • 13. LeBlanc G.A., et al, Draft Detailed Review Paper, State of the Science on Novel In Vitro and In Vivo Screening and Testing Methods and Endpoints for Evaluating Endocrine Disruptors, Contractor: RTI International, Draft #2, 2011
  • 14. Lee J.H., et al, PRX and LXR in hepatic Steatosis: a new dog and an old dog with new tricks, Mol. Pharm., 5(No 1),60-66, 2008
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David Bower
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