Pharmacological characterization of a novel liver X receptor agonist with partial LXRα activity and a favorable window in nonhuman primates

Journal of Pharmacology and Experimental Therapeutics

Volumn 352, Issue 2, 2015, Pages 305-314

  Kirchgessner, Todd G ^a   Martin, Richard ^b   Sleph, Paul ^a   Grimm, Denise ^a   Liu, Xiaoqin ^a   Lupisella, John ^a   Smalley, James ^a   Narayanan, Rangaraj ^a   Xie, Yinong ^b   Ostrowski, Jacek ^a   Cantor, Glenn H ^a   Mohan, Raju ^b   Kick, Ellen ^a  

^a BRISTOL MYERS SQUIBB RESEARCH AND DEVELOPMENT   (United States)

^b EXELIXIS INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 [2 (1 (2 CHLOROPHENYL) 1 METHYLETHYL) 1 (3' (METHYLSULFONYL) 4 BIPHENYLYL) 1H IMIDAZOL 4 YL] 2 PROPANOL; ABC TRANSPORTER A1; ABC TRANSPORTER G1; APOLIPOPROTEIN B; CHOLESTEROL ESTER TRANSFER PROTEIN; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; LIVER X RECEPTOR AGONIST; LIVER X RECEPTOR ALPHA; LIVER X RECEPTOR BETA; LOW DENSITY LIPOPROTEIN CHOLESTEROL; MESSENGER RNA; N (2,2,2 TRIFLUOROETHYL) N [4 (2,2,2 TRIFLUORO 1 HYDROXY 1 TRIFLUOROMETHYLETHYL)PHENYL]BENZENESULFONAMIDE; TRIACYLGLYCEROL; UNCLASSIFIED DRUG; 2-(2-(1-(2-CHLOROPHENYL)-1-METHYLETHYL)-1-(3'-(METHYLSULFONYL)-4-BIPHENYLYL)-1H-IMIDAZOL-4-YL)-2-PROPANOL; ABC TRANSPORTER; HYPOCHOLESTEROLEMIC AGENT; IMIDAZOLE DERIVATIVE; LIPID; LIVER X RECEPTOR; ORPHAN NUCLEAR RECEPTOR; SULFONE;

ABCA1 GENE; ABCG1 GENE; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; ATHEROSCLEROSIS; CHOLESTEROL BLOOD LEVEL; CHOLESTEROL TRANSPORT; CONTROLLED STUDY; DOSE TIME EFFECT RELATION; DRUG EFFECT; DRUG MECHANISM; DRUG POTENCY; EC50; GENE; GENE INDUCTION; HUMAN; IN VIVO STUDY; LIPID LIVER LEVEL; MACACA FASCICULARIS; MALE; NONHUMAN; PROTEIN BLOOD LEVEL; RECEPTOR BINDING; TRIACYLGLYCEROL BLOOD LEVEL; AGONISTS; ANIMAL; BLOOD; DOSE RESPONSE; DRUG EFFECTS; GENETICS; LIPOGENESIS; LIVER; METABOLISM; PARTIAL AGONISM;

ANIMALS; ANTICHOLESTEREMIC AGENTS; ATP-BINDING CASSETTE TRANSPORTERS; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG PARTIAL AGONISM; IMIDAZOLES; LIPIDS; LIPOGENESIS; LIVER; MACACA FASCICULARIS; MALE; ORPHAN NUCLEAR RECEPTORS; SULFONES; TRIGLYCERIDES;

EID: 84919726556     PISSN: 00223565     EISSN: 15210103     Source Type: Journal    
DOI: 10.1124/jpet.114.219923     Document Type: Article

References (36)

1. Albers M, Blume B, Schlueter T, Wright MB, Kober I, Kremoser C, Deuschle U, and Koegl M (2006) A novel principle for partial agonism of liver X receptor ligands. Competitive recruitment of activators and repressors. J Biol Chem 281:4920-4930.
2. Bradley MN, Hong C, Chen M, Joseph SB, Wilpitz DC, Wang X, Lusis AJ, Collins A, Hseuh WA, Collins JL, et al. (2007) Ligand activation of LXR beta reverses atherosclerosis and cellular cholesterol overload in mice lacking LXR alpha and apoE. J Clin Invest 117:2337-2346.
3. Carey MC (1978) Critical tables for calculating the cholesterol saturation of native bile. J Lipid Res 19:945-955.
4. Chiang JY, Kimmel R, and Stroup D (2001) Regulation of cholesterol 7alpha-hydroxylase gene (CYP7A1) transcription by the liver orphan receptor (LXRalpha). Gene 262:257-265.
5. Delmas PD, Bjarnason NH, Mitlak BH, Ravoux A-C, Shah AS, Huster WJ, Draper M, and Christiansen C (1997) Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopaual women. N Engl J Med 337:1641-1647.
6. Giannarelli C, Cimmino G, Connolly TM, Ibanez B, Ruiz JM, Alique M, Zafar MU, Fuster V, Feuerstein G, and Badimon JJ (2012) Synergistic effect of liver X receptor activation and simvastatin on plaque regression and stabilization: an magnetic resonance imaging study in a model of advanced atherosclerosis. Eur Heart J 33:264-273.
7. Groot PH, Pearce NJ, Yates JW, Stocker C, Sauermelch C, Doe CP, Willette RN, Olzinski A, Peters T, d'Epagnier D, et al. (2005) Synthetic LXR agonists increase LDL in CETP species. J Lipid Res 46:2182-2191.
8. Honzumi S, Shima A, Hiroshima A, Koieyama T, Ubukata N, and Terasaka N (2010) LXRalpha regulates human CETP expression in vitro and in transgenic mice. Atherosclerosis 212:139-145.
9. Inaba T, Matsuda M, Shimamura M, Takei N, Terasaka N, Ando Y, Yasumo H, Koishi R, Makishima M, and Shimomura I (2003) Angiopoietin-like protein 3 mediates hypertriglyceridemia induced by the liver X receptor. J Biol Chem 278:21344-21351.
10. Jakel H, Nowak M, Moitrot E, Dehondt H, Hum DW, Pennacchio LA, Fruchart-Najib J, and Fruchart JC (2004) The liver X receptor ligand T0901317 down-regulates APOA5 gene expression through activation of SREBP-1c. J Biol Chem 279:45462-45469.
11. Janowski BA, Grogan MJ, Jones SA,Wisely GB, Kliewer SA, Corey EJ, and Mangelsdorf DJ (1999) Structural requirements of ligands for the oxysterol liver X receptors LXRalpha and LXRbeta. Proc Natl Acad Sci USA 96:266-271.
12. Joseph SB, McKilligin E, Pei L, Watson MA, Collins AR, Laffitte BA, Chen M, Noh G, Goodman J, Hagger GN, et al. (2002) Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proc Natl Acad Sci USA 99:7604-7609.
13. Kick E, Martin R, Xie Y, Flatt B, Schweiger E, Wang TL, Busch B, Nyman M, Gu XH, Yan G, et al. (2014) Liver X Receptor (LXR) partial agonists: biaryl pyrazoles and imidazoles displaying LXR beta selectivity. Bioorg Med Chem Lett DOI:10.1016/j.bmcl.2014.11.029.
14. Laffitte BA, Repa JJ, Joseph SB, Wilpitz DC, Kast HR, Mangelsdorf DJ, and Tontonoz P (2001) LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes. Proc Natl Acad Sci U S A 98:507-512.
15. Lehmann JM, Kliewer SA, Moore LB, Smith-Oliver TA, Oliver BB, Su JL, Sundseth SS, Winegar DA, Blanchard DE, Spencer TA, et al. (1997) Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. J Biol Chem 272:3137-3140.
16. Lund EG, Peterson LB, Adams AD, Lam MH, Burton CA, Chin J, Guo Q, Huang S, Latham M, Lopez JC, et al. (2006) 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.
17. Luo Y and Tall AR (2000) Sterol upregulation of human CETP expression in vitro and in transgenic mice by an LXR element. J Clin Invest 105:513-520.
18. Peet DJ, Turley SD, Ma W, Janowski BA, Lobaccaro JM, Hammer RE, and Mangelsdorf DJ (1998) Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha. Cell 93:693-704.
19. Peng D, Hiipakka RA, Xie JT, Reardon CA, Getz GS, and Liao S (2010) Differential effects of activation of liver X receptor on plasma lipid homeostasis in wild-type and lipoprotein clearance-deficient mice. Atherosclerosis 208:126-133.
20. Quinet EM, Basso MD, Halpern AR, Yates DW, Steffan RJ, Clerin V, Resmini C, Keith JC, Berrodin TJ, Feingold I, et al. (2009) LXR ligand lowers LDL cholesterol in primates, is lipid neutral in hamster, and reduces atherosclerosis in mouse. J Lipid Res 50:2358-2370.
21. Quinet EM, Savio DA, Halpern AR, Chen L, Schuster GS, Gustafsson JA, Basso MD, and Nambi P (2006) Liver X receptor (LXR)-beta regulation in LXRalpha-deficient mice: implications for therapeutic targeting. Mol Pharmacol 70:1340-1349.
22. Repa JJ, Berge KE, Pomajzl C, Richardson JA, Hobbs H, and Mangelsdorf DJ (2002) Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors alpha and beta. J Biol Chem 277:18793-18800.
23. Rosenson RS, Brewer HB, Jr, Davidson WS, Fayad ZA, Fuster V, Goldstein J, Hellerstein M, Jiang XC, Phillips MC, Rader DJ, et al. (2012) Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport. Circulation 125:1905-1919.
24. Schultz JR, Tu H, Luk A, Repa JJ, Medina JC, Li L, Schwendner S, Wang S, Thoolen M, Mangelsdorf D, et al. (2000) Role of LXRs in control of lipogenesis. Genes Dev 14:2831-2838.
25. Szczepaniak LS, Nurenberg P, Leonard D, Browning JD, Reingold JS, Grundy S, Hobbs HH, and Dobbins RL (2005) Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab 288:E462-E468.
26. Terasaka N, Hiroshima A, Koieyama T, Ubukata N, Morikawa Y, Nakai D, and Inaba T (2003) T-0901317, a synthetic liver X receptor ligand, inhibits development of atherosclerosis in LDL receptor-deficient mice. FEBS Lett 536:6-11.
27. Tontonoz P and Mangelsdorf DJ (2003) Liver X receptor signaling pathways in cardiovascular disease. Mol Endocrinol 17:985-993.
28. Turley SD, Spady DK, and Dietschy JM (1995) Role of liver in the synthesis of cholesterol and the clearance of low density lipoproteins in the cynomolgus monkey. J Lipid Res 36:67-79.
29. Venkateswaran A, Laffitte BA, Joseph SB, Mak PA, Wilpitz DC, Edwards PA, and Tontonoz P (2000a) Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXR alpha. Proc Natl Acad Sci USA 97:12097-12102.
30. Venkateswaran A, Repa JJ, Lobaccaro JM, Bronson A, Mangelsdorf DJ, and Edwards PA (2000b) Human white/murine ABC8 mRNA levels are highly induced in lipid-loaded macrophages. A transcriptional role for specific oxysterols. J Biol Chem 275:14700-14707.
31. Vucic E, Calcagno C, Dickson SD, Rudd JH, Hayashi K, Bucerius J, Moshier E, Mounessa JS, Roytman M, Moon MJ, et al. (2012) Regression of inflammation in atherosclerosis by the LXR agonist R211945: a noninvasive assessment and comparison with atorvastatin. JACC Cardiovasc Imaging 5:819-828.
32. Wrobel J, Steffan R, Bowen SM, Magolda R, Matelan E, Unwalla R, Basso M, Clerin V, Gardell SJ, Nambi P, et al. (2008) Indazole-based liver X receptor (LXR) modulators with maintained atherosclerotic lesion reduction activity but diminished stimulation of hepatic triglyceride synthesis. J Med Chem 51:7161-7168.
33. Yu L, York J, von Bergmann K, Lutjohann D, Cohen JC, and Hobbs HH (2003) Stimulation of cholesterol excretion by the liver X receptor agonist requires ATPbinding cassette transporters G5 and G8. J Biol Chem 278:15565-15570.
34. Zelcer N, Hong C, Boyadjian R, and Tontonoz P (2009) LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor. Science 325:100-104.
35. Zelcer N and Tontonoz P (2006) Liver X receptors as integrators of metabolic and inflammatory signaling. J Clin Invest 116:607-614.
36. Zhang Y, Repa JJ, Gauthier K, and Mangelsdorf DJ (2001) Regulation of lipoprotein lipase by the oxysterol receptors, LXRalpha and LXRbeta. J Biol Chem 276:43018-43024.