N-acylthiadiazolines, a new class of liver X receptor agonists with selectivity for LXRβ

Journal of Medicinal Chemistry

Volumn 50, Issue 17, 2007, Pages 4255-4259

  Molteni, Valentina ^a   Li, Xiaolin ^a   Nabakka, Juliet ^a   Liang, Fang ^a   Wityak, John ^a   Koder, Alan ^a   Vargas, Leo ^a   Romeo, Russell ^a   Mitro, Nico ^a,b   Mak, Puiying A ^a   Seidel, H Martin ^a   Haslam, Jennifer A ^a   Chow, Donald ^a   Tuntland, Tove ^a   Spalding, Tracy A ^a   Brock, Ansgar ^a   Bradley, Michelle ^c   Castrillo, Antonio ^c   Tontonoz, Peter ^c   Saez, Enrique ^a,b  

^a GENOMICS INSTITUTE OF THE NOVARTIS RESEARCH FOUNDATION   (United States)

^b SCRIPPS RESEARCH INSTITUTE   (United States)

^c UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ABC TRANSPORTER A1; APOLIPOPROTEIN A1; CHOLESTEROL; LIVER X RECEPTOR ALPHA; LIVER X RECEPTOR BETA; RECEPTOR SUBTYPE; STEROL REGULATORY ELEMENT BINDING PROTEIN 1C; THIADIAZOLE DERIVATIVE;

ANIMAL CELL; ANIMAL EXPERIMENT; ARTICLE; CHOLESTEROL TRANSPORT; CONTROLLED STUDY; DRUG EFFICACY; DRUG POTENCY; DRUG RECEPTOR BINDING; DRUG SELECTIVITY; FLUORESCENCE RESONANCE ENERGY TRANSFER; HUMAN; HUMAN CELL; MACROPHAGE; MALE; MOUSE; NONHUMAN; RECEPTOR UPREGULATION; STRUCTURE ACTIVITY RELATION; X RAY CRYSTALLOGRAPHY;

ANIMALS; APOLIPOPROTEIN A-I; ATP-BINDING CASSETTE TRANSPORTERS; CELL LINE; CHOLESTEROL; CRYSTALLOGRAPHY, X-RAY; DNA-BINDING PROTEINS; HEPATOCYTES; HUMANS; MACROPHAGES, PERITONEAL; MICE; MICE, KNOCKOUT; RECEPTORS, CYTOPLASMIC AND NUCLEAR; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; THIADIAZOLES;

EID: 34548128301     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm070453f     Document Type: Article

References (30)

1. Kalaany, N. Y.; Mangelsdorf, D. J. LXRS and FXR: The yin and yang of cholesterol and fat metabolism. Ann. Rev. Physiol. 2006, 68, 159-191.
2. Tontonoz, P.; Mangelsdorf, D. J. Liver X receptor signaling pathways in cardiovascular disease. Mol. Endocrinol. 2003, 17 (6), 985-993.
3. Janowski, B. A.; Willy, P. J.; Devi, T. R.; Falck, J. R.; Mangelsdorf, D. J. An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha. Nature 1996, 383 (6602), 728-731.
4. Lehmann, J. M.; Kliewer, S. A.; Moore, L. B.; Smith-Oliver, T. A.; Oliver, B. B.; Su, J. L.; Sundseth, S. S.; Winegar, D. A.; Blanchard, D. E.; Spencer, T. A.; Willson, T. M. Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. J. Biol. Chem. 1997, 272 (6), 3137-3140.
5. Mitro, N.; Mak, P. A.; Vargas, L.; Godio, C.; Hampton, E.; Molteni, V.; Kreusch, A.; Saez, E. The nuclear receptor LXR is a glucose sensor. Nature 2007, 445, 219-223.
6. Collins, J. L.; Fivush, A. M.; Watson, M. A.; Galardi, C. M.; Lewis, M. C.; Moore, L. B.; Parks, D. J.; Wilson, J. G.; Tippin, T. K.; Binz, J. G.; Plunket, K. D.; Morgan, D. G.; Beaudet, E. J.; Whitney, K. D.; Kliewer, S. A.; Willson, T. M. Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary amines. J. Med. Chem. 2002, 45 (10), 1963-1966.
7. 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.; Shan, B. Role of LXRs in control of lipogenesis. Genes Dev. 2000, 14 (22), 2831-2838.
8. Jaye, M. C.; Krawiec, J. A.; Campobasso, N.; Smallwood, A.; Qiu, C.; Lu, Q.; Kerrigan, J. J.; De Los Frailes Alvaro, M.; Laffitte, B.; Liu, W. S.; Marino, J. P., Jr.; Meyer, C. R.; Nichols, J. A.; Parks, D. J.; Perez, P.; Sarov-Blat, L.; Seepersaud, S. D.; Steplewski, K. M.; Thompson, S. K.; Wang, P.; Watson, M. A.; Webb, C. L.; Haigh, D.; Caravella, J. A.; Macphee, C. H.; Willson, T. M.; Collins, J. L. Discovery of substituted maleimides as liver X receptor agonists and determination of a ligand-bound crystal structure. J. Med. Chem. 2005, 48 (17), 5419-5422.
9. Hu, B.; Collini, M.; Unwalla, R.; Miller, C.; Singhaus, R.; Quinet, E.; Savio, D.; Halpern, A.; Basso, M.; Keith, J.; Clerin, V.; Chen, L.; Resmini, C.; Liu, Q. Y.; Feingold, I.; Huselton, C.; Azam, F.; Farnegardh, M.; Enroth, C.; Bonn, T.; Goos-Nilsson, A.; Wilhelmsson, A.; Nambi, P.; Wrobel, J. Discovery of phenyl acetic acid substituted quinolines as novel liver X receptor agonists for the treatment of atherosclerosis. J. Med. Chem. 2006, 49 (21), 6151-6154.
10. Quinet, E. M.; Savio, D. A.; Halpern, A. R.; Chen, L.; Miller, C. P.; Nambi, P. Gene-selective modulation by a synthetic oxysterol ligand of the liver X receptor. J. Lipid Res. 2004, 45 (10), 1929-1942.
11. Collins, J. L. Therapeutic opportunities for liver X receptor modulators. Curr. Opin. Drug Discovery Dev. 2004, 7 (5), 692-702.
12. Joseph, S. B.; Castrillo, A.; Laffitte, B. A.; Mangelsdorf, D. J.; Tontonoz, P. Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. Nat. Med. 2003, 9 (2), 213-219.
13. Joseph, S. B.; McKilligin, E.; Pei, L.; Watson, M. A.; Collins, A. R.; Laffitte, B. A.; Chen, M.; Noh, G.; Goodman, J.; Hagger, G. N.; Tran, J.; Tippin, T. K.; Wang, X.; Lusis, A. J.; Hsueh, W. A.; Law, R. E.; Collins, J. L.; Willson, T. M.; Tontonoz, P. Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proc. Natl. Acad. Sci. U.S.A. 2002, 99 (11), 7604-7609.
14. Laffitte, B. A.; Chao, L. C.; Li, J.; Walczak, R.; Hummasti, S.; Joseph, S. B.; Castrillo, A.; Wilpitz, D. C.; Mangelsdorf, D. J.; Collins, J. L.; Saez, E.; Tontonoz, P. Activation of liver X receptor improves glucose tolerance through coordinate regulation of glucose metabolism in liver and adipose tissue. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 5419-5424.
15. Cao, G.; Liang, Y.; Broderick, C. L.; Oldham, B. A.; Beyer, T. P.; Schmidt, R. J.; Zhang, Y.; Stayrook, K. R.; Suen, C.; Otto, K. A.; Miller, A. R.; Dai, J.; Foxworthy, P.; Gao, H.; Ryan, T. P.; Jiang, X. C.; Burris, T. P.; Eacho, P. I.; Etgen, G. J. Antidiabetic action of a liver X receptor agonist mediated by inhibition of hepatic gluconeogenesis. J. Biol. Chem. 2003, 278 (2), 1131-1136.
16. Whitney, K. D.; Watson, M. A.; Collins, J. L.; Benson, W. G.; Stone, T. M.; Numerick, M. J.; Tippin, T. K.; Wilson, J. G.; Winegar, D. A.; Kliewer, S. A. Regulation of cholesterol homeostasis by the liver X receptors in the central nervous system. Mol. Endocrinol. 2002, 16 (6), 1378-1385.
17. Lund, E. G.; Menke, J. G.; Sparrow, C. P. Liver X receptor agonists as potential therapeutic agents for dyslipidemia and atherosclerosis. Art. Thromb. Vasc. Biol. 2003, 23, (7), 1169-1177.
18. Lund, E. G.; Peterson, L. B.; Adams, A. D.; Lam, M. H.; Burton, C. A.; Chin, J.; Guo, Q.; Huang, S.; Latham, M.; Lopez, J. C.; Menke, J. G.; Milot, D. P.; Mitnaul, L. J.; Rex-Rabe, S. E.; Rosa, R. L.; Tian, J. Y.; Wright, S. D.; Sparrow, C. P. 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. 2006, 71 (4), 453-463.
19. Quinet, E. M.; Savio, D. A.; Halpern, A. R.; Chen, L.; Schuster, G. U.; Gustafsson, J. A.; Basso, M. D.; Nambi, P. Liver X receptor (LXR)-beta regulation in LXRalpha-deficient mice: Implications for therapeutic targeting. Mol. Pharm. 2006, 70 (4), 1340-1349.
20. Williams, S.; Bledsoe, R. K.; Collins, J. L.; Boggs, S.; Lambert, M. H.; Miller, A. B.; Moore, J.; McKee, D. D.; Moore, L.; Nichols, J.; Parks, D.; Watson, M.; Wisely, B.; Willson, T. M. X-ray crystal structure of the liver X receptor beta ligand binding domain: Regulation by a histidine-tryptophan switch. J. Biol. Chem. 2003, 278 (29), 27138-27143.
21. Svensson, S.; Ostberg, T.; Jacobsson, M.; Norstrom, C.; Stefansson, K.; Hallen, D.; Johansson, I. C.; Zachrisson, K.; Ogg, D.; Jendeberg, L. Crystal structure of the heterodimeric complex of LXRalpha and RXRbeta ligand-binding domains in a fully agonistic conformation. EMBO J. 2003, 22 (18), 4625-4633.
22. Hoerer, S.; Schmid, A.; Heckel, A.; Budzinski, R. M.; Nar, H. Crystal structure of the human liver X receptor beta ligand-binding domain in complex with a synthetic agonist. J. Mol. Biol. 2003, 334 (5), 853-861.
23. Laffitte, B. A.; Joseph, S. B.; Walczak, R.; Pei, L.; Wilpitz, D. C.; Collins, J. L.; Tontonoz, P. Autoregulation of the human liver X receptor alpha promoter. Mol. Cell. Biol. 2001, 21 (22), 7558-7568.
24. 2-1, 3,4-Thiadiazolines at the 4-position. J. Chem. Soc., Chem. Commun. 1982, 3, 188-189.
25. Evans, D. M.; Hill, L.; Taylor, D. R. Thiadiazoles and dihydrothiadiazoles. J. Chem. Soc., Perkin. Trans. 1 1986, 8, 1499-1505.
26. Joseph, S. B.; Bradley, M. N.; Castrillo, A.; Bruhn, K. W.; Mak, P. A.; Pei, L.; Hogenesch, J.; O'Connell, R, M.; Cheng, G.; Saez, E.; Miller, J. F.; Tontonoz, P. LXR-dependent gene expression is important for macrophage survival and the innate immune response. Cell 2004, 119 (2), 299-309.
27. Janowski, B. A.; Grogan, M. J.; Jones, S. A.; Wisely, G. B.; Kliewer, S. A.; Corey, E. J.; Mangelsdorf, D. J. Structural requirements of ligands for the oxysterol liver X receptors LXRalpha and LXRbeta. Proc. Natl. Acad. Sci. U.S.A. 1999, 96 (1), 266-271.
28. DeBlasi, A.; O'Reilly, K.; Motulsky, H. J. Calculating receptor number from binding experiments using same compound as radioligand and competitor. Trends Pharmacol. Sci. 1989, 10 (6), 227-229.
29. Compound 2 was tested for stability in human liver microsomes (1 μM). After 30 minutes, 70% of the compound was still present.
30. 1/2 was 4.5 hours.