Therapeutic opportunities for liver X receptor modulators

Current Opinion in Drug Discovery and Development

Volumn 7, Issue 5, 2004, Pages 692-702

  Collins, Jon L ^a  

^a GLAXOSMITHKLINE   (United States)

Author keywords

Atherosclerosis; Diabetes; Inflammation; LXR; Modulator; Nuclear receptor

Indexed keywords

3 [3 [[2 CHLORO 3 (TRIFLUOROMETHYL)BENZYL](2 DIPHENYLETHYL)AMINO]PROPOXY]PHENYLACETIC ACID; 4 PYRIMIDINONE DERIVATIVE; ABC TRANSPORTER; AMIDE; ANILINE DERIVATIVE; CELL NUCLEUS RECEPTOR; GW 1519; LIGAND; LIVER X RECEPTOR; LIVER X RECEPTOR ALPHA; LIVER X RECEPTOR BETA; LN 7033; PODOCARPIC ACID DERIVATIVE; PURINE DERIVATIVE; PYRIDONE DERIVATIVE; QUINAZOLINE DERIVATIVE; SULFIDE; SULFONE; T 1317; THIOL DERIVATIVE; THIOUREA DERIVATIVE; TRANSCRIPTION FACTOR; UNCLASSIFIED DRUG;

ATHEROSCLEROSIS; CARDIOVASCULAR DISEASE; CHOLESTEROL METABOLISM; CRYSTAL STRUCTURE; DEGENERATIVE DISEASE; DIABETES MELLITUS; DRUG TARGETING; FATTY ACID METABOLISM; GENE EXPRESSION REGULATION; HUMAN; INFLAMMATION; LIPOGENESIS; NONHUMAN; REVIEW; SIGNAL TRANSDUCTION;

DNA-BINDING PROTEINS; DRUG DELIVERY SYSTEMS; DRUG DESIGN; HUMANS; RECEPTORS, CYTOPLASMIC AND NUCLEAR; SIGNAL TRANSDUCTION; TECHNOLOGY, PHARMACEUTICAL;

EID: 4944221668     PISSN: 13676733     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (74)

1. Peet DJ, Janowski BA, Mangelsdorf DJ: The LXRs: A new class of oxysterol receptors. Curr Opin Genet Dev (1998) 8(5):571-575.
2. Lehmann JM, Kliewer SA, Moore LB, Smith-Oliver TA, Oliver BB, Su J-L, Sundseth SS, Winegar DA, Blanchard DE, Spencer TA, Willson TM: Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. J Biol Chem (1997) 272(6):3137-3140.
3. Janowski BA, Willy PJ, Devi TR, Falck JR, Mangelsdorf DJ: An oxysterol signalling pathway mediated by the nuclear receptor LXRα. Nature (1996) 383(6602):728-731.
4. Forman B, Ruan B, Chen J, Schroepfer G, Evans R: The orphan nuclear receptor LXRα is positively and negatively regulated by distinct products of mevalonate metabolism. Proc Natl Acad Sci USA (1997) 94(20):10588-10593.
5. Fu X, Menke JG, Chen Y, Zhou G, MacNaul KL, Wright SD, Sparrow CP, Lund EG: 27-Hydroxycholesterol is an endogenous ligand for liver X receptor in cholesterol-loaded cells. J Biol Chem (2001) 276(42):38378-38387.
6. Spencer TA, Li D, Russel JS, Collins JL, Bledsoe RK, Consler TG, Moore LB, Galardi CM, McKee DD, Moore JT, Watson MA et al: Pharmacophore analysis of the nuclear oxysterol receptor LXRα. J Med Chem (2001) 44(6):886-897.
7. Janowski BA, Grogan MJ, Jones SA, Wisely GB, Kliewer SA, Corey EJ, Mangelsdorf DJ: Structural requirements of ligands for the oxysterol liver X receptors LXRα and LXRβ. Proc Natl Acad Sci USA (1999) 96(1):266-271.
8. Peet DJ, Turley SD, Ma W, Janowski BA, Lobaccaro J-M, Hammer RE, Mangelsdorf DJ: Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXRα. Cell (1998) 93(5):693-704.
9. Schultz JR, Tu H, Luk A, Repa JJ, Medina JC, Li L, Schwendner S, Wang S, Thoolen M, Mangelsdorf DJ, Lustig KD et al: Role of LXRs in control of lipogenesis. Gene Dev (2000) 14(22):2831-2838.
10. Collins JL, Fivush AM, Watson MA, Galardi CM, Lewis MC, Moore LB, Parks DJ, Wilson JG, Tippin TK, Binz JG, Plunkel KD et al: Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary amines. J Med Chem (2002) 45(10):1963-1966.
11. Tontonoz P, Mangelsdorf DJ: Liver X receptor signaling pathways in cardiovascular disease. Mol Endocrinol (2003) 17(6):985-993. An excellent review that highlights the role of the LXRs in cardiovascular disease.
12. Glass CK, Witztum J: Atherosclerosis: The road ahead. Cell (2001) 104(4):503-516.
13. McNeish J, Aiello RJ, Guyot D, Turi T, Gabel C, Aldinger C, Hoppe KL, Roach ML, Royer LJ, de Wet J, Broccardo C et al: High density lipoprotein deficiency and foam cell accumulation in mice with targeted disruption of ATP-binding cassette transporter-1. Proc Natl Acad Sci USA (2000) 97(8):4245-4250.
14. Wellington CL, Brunham LR, Zhou S, Singaraja RR, Visscher H, Gelfer A, Ross C, James E, Liu G, Huber MT, Yang Y-Z et al: Alterations of plasma lipids in mice via adenoviral-mediated hepatic overexpression of human ABCA1. J Lipid Res (2003) 44(8):1470-1480.
15. Rust S, Rosier M, Funke H, Real J, Amoura Z, Piette JC, Deleuze JF, Brewer HB, Duverger N, Denefle P, Assmann G: Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nat Genet (1999) 22(4):352-355.
16. Brooks-Wilson A, Marcil M, Clee SM, Zhang LH, Roomp K, van Dam M, Yu L, Brewer C, Collins JA, Molhuizen HO, Loubser O et al: Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nat Genet (1999) 22(4):336-345.
17. Bodzioch M, Orso E, Klucken J, Langmann T, Bottcher A, Diederich W, Drobnik W, Barlage S, Buchler C et al: The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nat Genet (1999) 22(4):347-351.
18. Clee SM, Kastelein JJ, Van Dam M, Marcil M, Roomp K, Zwarts KY, Collins JA, Roelants R, Tamasawa N, Stulc T, Suda T et al: Age and residual cholesterol efflux affect HDL cholesterol levels and coronary artery disease in ABCA1 heterozygotes. J Clin Invest (2000) 106(10):1263-1270.
19. 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 (2000) 289(5484):1524-1529. This seminal paper uncovered the role of LXRα and LXRβ in the regulation of ABCA1 expression in the macrophage and cholesterol absorption in the intestine.
20. Joseph SB, McKilligin E, Pei L, Watson MA, Collins AR, Laffitte BA, Chen M, Noh G, Goodman J, Hagger GN, Tran J et al: Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proc Natl Acad Sci USA (2002) 99(11):7604-7609. The first demonstration that a non-steroidal LXR agonist can prevent the formation of atherosclerosis in animal models.
21. Terasaka N, Hiroshima A, Koieyama T, Ubukata N, Morikawa Y, Nakai D, Inaba T: T-0901317, a synthetic liver X receptor ligand, inhibits development of atherosclerosis in LDL receptor-deficient mice. FEBS Lett (2003) 536(1-3):6-11.
22. Wagner BL: Metabolic regulation by orphan nuclear receptors. Nuclear Receptors: Orphan Brothers Keystone Symposium, Keystone, CO, USA (2004):Abs 020.
23. Repa JJ, Berge KE, Pomajzl C, Richardson JA, Hobbs H, Mangelsdorf DJ: Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors α and β. J Biol Chem (2002) 277(21):18793-18800.
24. Klucken J, Buchler C, Orso E, Kaminski WE, Porsch-Ozcurumez M, Liebisch G, Kapinsky M, Diederich W, Drobnik W, Dean M, Allikmets R et al: ABCG1 (ABC8), the human homolog of the Drosophila white gene, is a regulator of macrophage cholesterol and phospholipid transport. Proc Natl Acad Sci USA (2000) 97(2):817-822.
25. Graf GA, Li W-P, Gerard RD, Gelissen I, White A, Cohen JC, Hobbs HH: Coexpression of ATP-binding cassette proteins ABCG5 and ABCG8 permits their transport to the apical surface. J Clin Invest (2002) 110(5):659-669.
26. Graf GA, Yu L, Li W-P, Gerard R, Tuma PL, Cohen JC, Hobbs HH: ABCG5 and ABCG8 are obligate heterodimers for protein trafficking and biliary cholesterol excretion. J Biol Chem (2003) 278(48):48275-48282.
27. Berge KE, Tian H, Graf GA, Yu L, Grishin NV, Schultz J, Kwiterovich P, Shan B, Barnes R, Hobbs HH: Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science (2000) 280(5497):1771-1775.
28. Lee M-H, Lu K, Patel SB: Genetic basis of sitosterolemia. Curr Opin Lipidol (2001) 12(2):141-149.
29. Joseph SB, Castrillo A, Laffitte BA, Mangelsdorf DJ, Tontonoz P: Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. Nat Med (2003) 9(2):213-219. Paper demonstrating that LXR agonists repress pro-inflammatory gene expression via an LXR-dependent NFκB signaling pathway, suggesting that LXR agonists could be valuable agents for the treatment of inflammation.
30. Komuves LG, Schmuth M, Fowler AJ, Elias PM, Hanley K, Man M-Q, Moser AH, Lobaccaro, J-M, Williams ML, Mangelsdorf DJ, Feingold KR: Oxysterol stimulation of epidermal differentiation is mediated by liver X receptor-β in murine epidermis. J Invest Dermatol (2002) 118(1):25-34.
31. Fowler AJ, Sheu MY, Schmuth M, Kao J, Fluhr JW, Rhein L, Collins JL, Willson TM, Mangelsdorf DJ, Elias PM, Feingold KR: Liver X receptor activators display anti-inflammatory activity in irritant and allergic contact dermatitis models: Liver-X-receptor-spacific inhibition of inflammation and primary cytokine production. J Invest Dermatol (2003) 120(2):246-255.
32. Stulnig TM, Steffensen KR, Gao H, Reimers M, Dahlman-Wright K, Schuster GU, Gustafsson J-A: Novel roles of liver X receptors exposed by gene expression profiling in liver and adipose tissue. Mol Pharmacol (2002) 62(6):1299-1305. Paper providing the initial data demonstrating that T-1317 represses the expression of genes involved in gluconeogenesis including PEPCK, fructose-1,6-bisphosphatase and G6P.
33. Laffitte BA, Chao LC, Li J, Walczak R, Hummasti S, Joseph SB, Castrillo A, Wilpitz DC, Mangelsdorf DJ, Collins JL, Saez E et al: Activation of liver X receptor improves glucose tolerance through coordinate regulation of glucose metabolism in liver and adipose tissue. Proc Natl Acad Sci USA (2003) 100(9):5419-5424. Paper demonstrating that GW-3965 represses the expression of genes involved in gluconeogenesis and improves glucose tolerance in an animal model of diet-induced obesity and insulin resistance.
34. Cao G, Liang Y, Broderick CL, Oldham BA, Beyer TP, Schmidt RJ, Zhang Y, Stayrook KR, Suen C, Otto KA, Miller AR et al: Antidiabetic action of a liver X receptor agonist mediated by inhibition of hepatic gluconeogenesis. J Biol Chem (2003) 278(2):1131-1136. Paper demonstrating that T-1317 represses the expression of genes involved in gluconeogenesis and improves glucose tolerance in db/db mice and ZDF rats. Moreover, the paper shows that T-1317 improves insulin sensitivity in fa/fa rats subjected to an oral glucose tolerance test.
35. Wang L, Schuster GU, Hultenby K, Zhang Q, Andersson S, Gustafsson J-A: Liver X receptors in the central nervous system: From lipid homeostasis to neuronal degeneration. Proc Natl Acad Sci USA (2002) 99(21):13878-13883. Paper providing data from LXRα/β double-knockout mouse and suggesting that LXR agonists might be useful for the treatment of neurodegenerative diseases.
36. Whitney KD, Watson MA, Collins JL, Benson WG, Stone TM, Numerick MJ, Tippin TK, Wilson JG, Winegar DA, Kliewer SA: Regulation of cholesterol homeostasis by the liver X receptors in the central nervous system. Mol Endocrinol (2002) 16(6):1378-1385. Paper demonstrating that T-1317 induces the expression of ABCA1 in vitro and in vivo and enhances cholesterol efflux in primary astrocyte cultures, suggesting that LXR agonists can regulate cholesterol homestasis in the CNS.
37. Koldamova RP, Lefterov IM, Ikonomovic MD, Skoko J, Lefterov PL, Isanski BA, DeKosky ST, Lazo JS: 22R-Hydroxycholesterol and 9-cis-retinoic acid induce ATP-binding cassette transporter A1 expression and cholesterol efflux in brain cells and decrease amyloid β secretion. J Biol Chem (2003) 278(15):13244-13256.
38. Fukumoto H, Deng A, Irizarry MC, Fitzgerald ML, Rebeck GW: Induction of the cholesterol transporter ABCA1 in central nervous system cells by liver X receptor agonists increases secreted Aβ levels. J Biol Chem (2002) 277(50):48508-48513.
39. Sun Y, Yao J, Kim T-W, Tall AR: Expression of liver X receptor target genes decreases cellular amyloid β peptide secretion. J Biol Chem (2003) 278(30):27688-27694.
40. Liang Y, Lin S, Beyer TP, Zhang Y, Wu X, Bales KR, DeMattos RB, May PC, Li SD, Jiang X-C, Eacho PI et al: A liver X receptor and retinoid X receptor heterodimer mediates apolipoprotein E expression, secretion and cholesterol homeostasis in astrocytes. J Neurochem (2004) 88(3):623-634. Paper demonstrating that T-1317 increases apoE mRNA and protein expression in vitro and in vivo, reinforcing the idea that LXR modulators may be effective agents for the treatment of Alzheimer's disease and other neurological diseases.
41. Repa JJ, Liang G, Ou J, Bashmakov Y, Lobaccaro J-M, Shimomura I, Shan B, Brown MS, Goldstein JL, Mangelsdorf DJ: Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRα and LXRβ. Gene Dev (2000) 14(22):2819-2830. This paper, along with reference [42•], provides the first data demonstrating that the LXRs induce SREBP-1c expression and promote lipogenesis in the liver.
42. Schultz JR, Tu H, Luk A, Repa JJ, Medina JC, Li L, Schwendner S, Wang S, Thoolen M, Mangelsdorf DJ, Lustig KD et al: Role of LXRs in control of lipogenesis. Gene Dev (2000) 14(22):2831-2838. This paper, along with reference [41•], provides the first data demonstrating that the LXRs induce SREBP-1c expression and promote lipogenesis in the liver.
43. Chisholm JW, Hong J, Mills SA, Lawn RM: The LXR ligand T0901317 induces severe lipogenesis in the db/db diabetic mouse. J Lipid Res (2003) 44(11):2039-2048. Paper demonstrating that the effects of T-1317 on hepatic lipogenesis are exacerbated in animal models of diabetes.
44. Liang G, Yang J, Norton JD, Hammer RE, Goldstein JL, Brown MS: Diminished hepatic response to fasting/refeeding and liver X receptor agonists in mice with selective deficiency of sterol regulatory element-binding protein-1c. J Biol Chem (2002) 277(11):9520-9528. Paper providing data showing that SREBP-1c is a primary contributor to the LXRα/β agonist-mediated accumulation of triglycerides in the rodent liver. Additionally, the paper demonstrates that upregulation of SREBP-1c expression by T-1317 accounts for approximately 70% of the induction of FAS by LXRα/β agonists. The remaining 30% may be due to direct regulation of FAS by LXRα (see reference [45]). The data suggests identification of an LXR modulator that does not upregulate SREBP-1c, and FAS may provide a compound with an improved therapeutic window as compared to first-generation LXRα/β agonists.
45. Joseph SB, Laffitte BA, Patel PH, Watson MA, Matsukuma KE, Walczak R, Collins JL, Osborne TF, Tontonoz P: Direct and indirect mechanisms for regulation of fatty acid synthase gene expression by liver X receptors. J Biol Chem (2002) 277(13):11019-11025.
46. Alberti S, Schuster G, Parini P, Feltkamp D, Diczfalusy U, Rudling M, Angelin B, Bjorkhem I, Pettersson S, Gustafsson J-A: Hepatic cholesterol metabolism and resistance to dietary cholesterol in LXR β-deficient mice. J Clin Invest (2001) 107(5):565-573.
47. Williams S, Bledsoe RK, Collins JL, Boggs S, Lambert MH, Miller AB, Moore J, McKee DD, Moore L, Nichols J, Parks D et al: X-ray crystal structure of the liver X receptor β ligand binding domain: Regulation by a histidine-tryptophan switch. J Biol Chem (2003) 278(29):27138-27143. The first literature report describing the three-dimensional crystal structures of eCH and T-1317 bound to LXRβ. Crystallographic and mutagenesis data suggest the different ligands that activate LXR through unique mechanisms, which may lead to differential co-regulator recruitment and/or functional activity.
48. Färnegȧrdh M, Bonn T, Sun S, Ljunggren J, Ahola H, Wilhelmsson A, Gustafsson J-A, Carlquist M: The three-dimensional structure of the liver X receptor β reveals a flexible ligand-binding pocket that can accommodate fundamentally different ligands. J Biol Chem (2003) 278(40):38821-38828. The first literature report describing the three-dimensional crystal structure of GW-3965 bound to LXRβ. The large LBP combined with the different shapes induced with the different ligands suggests the LXRs will be good targets for modulator design.
49. Hoerer S, Schmid A, Heckel A, Budzinski R-M, Nar H: Crystal structure of the human liver X receptor β ligand-binding domain in complex with a synthetic agonist. J Mol Biol (2003) 334(5):853-861.
50. Svensson S, Oestberg T, Jacobsson M, Norstroem C, Stefansson K, Hallen D, Johansson IC, Zachrisson K, Ogg D, Jendeberg L: Crystal structure of the heterodimeric complex of LXRα and RXRα ligand-binding domains in a fully agonistic conformation. EMBO J (2003) 22(18):4625-4633.
51. Song C, Liao S: Cholestenoic acid is a naturally occurring ligand for liver X receptor α. Endocrinology (2000) 141(11):4180-4184.
52. Chin J, Adams AD, Bouffard A, Green A, Lacson RG, Smith T, Fischer PA, Menke JG, Sparrow CP, Mitnaul LJ: Miniaturization of cell-based β-lactamase-dependent FRET assays to ultra-high throughput formats to identify agonists of human liver X receptors. Assay Drug Dev Technol (2003) 1(6):777-787. Paper describing the identification of 1-PH as a > 100-fold LXRα-selective agonist. Confirmation of this data by other research groups is warranted.
53. Menke JG, MacNaul KL, Hayes NS, Baffic J, Chao Y-S, Elbrecht A, Kelly LJ, Lam M-H, Schmidt A, Sahoo S, Wang J et al: A novel liver X receptor agonist establishes species differences in the regulation of cholesterol 7α-hydroxylase (CYP7a). Endocrinology (2002) 143(7):2548-2558.
54. Sparrow CP, Baffic J, Lam M-H, Lund EG, Adams AD, Fu X, Hayes N, Jones AB, Macnaul KL, Ondeyka J, Singh S et al: A potent synthetic LXR agonist is more effective than cholesterol loading at inducing ABCA1 mRNA and stimulating cholesterol efflux. J Biol Chem (2002) 277(12):10021-10027.
55. PHARMACIA CORP (Becker DP, Decrescenzo GA, Malecha JW, Miyashiro JM, Van Camp JA, Collins JT): Sulfone liver X-receptor modulators. WO-03099775 (2003).
56. PHARMACIA CORP (Van Camp JA, Malecha JW, Miyashiro JM, Decrescenzo GA, Collins JT, Kalman MJ): Anilino liver X receptor modulators. WO-03099769 (2003).
57. CHUGAI SEIYAKU KABUSHIKI KAISHA (Arrhenius T, Cheng J-F, Nadzan AM): LXR modulators for the treatment of cardiovascular diseases. WO-03090732 (2003).
58. CHUGAI SEIYAKU KABUSHIKI KAISHA (Arrhenius T, Cheng J-F, Huang Y, Nadzan AM): LXR modulators. WO-03090869 (2003).
59. X-CEPTOR THERAPEUTICS INC/SANKYO CO LTD (Kaneko S, Watanabe T, Oda K, Mohan R, Schweiger EJ, Martin R): Fused-ring pyrimidin-4(3H)-one derivatives, processes for the preparation and uses thereof. WO-03106435 (2003).
60. SMITHKUNE BEECHAM CORP (Thompson SK, Kallander LS, Ma C, Marino JP, Lee D): Acid and ester compounds and methods of using the same. WO-03082802 (2003).
61. SMITHKLINE BEECHAM CORP (Thompson SK, Frazee JS, Kallander LS, Ma C, Marino JP, Neeb MJ, Bhat A, Mcatee JJ, Stavenger RA): Compounds and methods. WO-03082205 (2003).
62. SMITHKLINE BEECHAM CORP (Thompson SK, Frazee JS, Kallander LS, Ma C, Marino JP, Neeb MJ, Bhat A): Compounds and methods. WO-03082192 (2003).
63. TULARIK INC (Jian XY, Kayser F, Kopecky DJ, Mckendry S, Piper DE, Shiau AK): Arylsulfonamidobenzylic compounds. WO-03063576 (2003).
64. MERCK & CO (Jones AB, Adams AD, Green AI, Huang SY, Tse B, Gutteridge CE, Cheng Y): Therapeutic compounds for treating dyslipidemic conditions. WO-2004011448 (2004).
65. MERCK & Co (Adams AD, Tse B, Huang SY, Jones BA): Therapeutic compounds for treating dyslipidemic conditions. WO-03045382 (2003).
66. MERCK & CO (Jones AB, Adams AD, Tse B, Huang SY, Green A): Therapeutic compounds for treating dyslipidemic conditions. WO-03053352 (2003).
67. ELI LILLY & Co (Burris TP, Cao G, Cullinan GJ, Eacho PI, McCowan JR, Yu K-L): Tricyclic compounds useful for modulating LXR. WO-03031408 (2003).
68. PHARMACIA CORP (Nizal CS, Dalton CR, Malecha JW, Tollefson MB, Vancamp JA, Cox PB): Aromatic liver X-receptor modulators. WO-2004026816 (2004).
69. PHARMACIA CORP (Chandrakumar NS, Dalton CR, Malecha JW, Tollefson MB, Vancamp JA, Cox PB): Aromatic thioether liver X-receptor modulators. WO-03059874 (2003).
70. CHUGAI YAKU KABUSHIKI KAISHA (Arrhenius T, Cheng J-F, Nadzan AM, Wilson M): Preparation of mercaptothiazoles as liver X receptor (LXR) modulators. WO-03090746 (2003).
71. X-CEPTOR THERAPEUTICS INC (Bayne CD, Johnson AT, Lu S-P, Mohan R, Griffith RC): Modulators of LXR. WO-03059884 (2003).
72. GLAXO GROUP LTD (Boggs S, Collins JL, Fivush A, Stewart EL, Willson TM): Purine derivatives as liver X receptor agonists. WO-2004009091 (2004).
73. PHENEX PHARMACEUTICALS AG (Kober I, Albers M, Koegl M, Blume B, Deuschle U, Kremoser C): 4-Oxo-quinazoline LXR nuclear receptor binding compounds. EP-01398032 (2004). Patent disclosing the structure of LN-7033 and providing data showing that LN-7033 selectively upregulates ABCA1 versus SREBP-1c/FAS. Moreover, LN-7033 induces cholesterol efflux yet does not induce triglyceride biosynthesis in a liver cell line.
74. PHENEX PHARMACEUTICALS AG (Deuschle U, Kögl M, Blume B, Albers M, Kober I): Novel 2-amino-4-oxoquinazolones as LXR nuclear receptor binding compounds with partial agonistic properties. WO-2004024161 (2004). Patent disclosing the structures of additional analogs in the 2-amino-4-oxoquinazolone chemical series. Additional biological data are also provided.