Modeling, synthesis, and biological evaluation of potential retinoid X receptor (RXR) selective agonists: Novel analogues of 4-[1-(3,5,5,8,8- Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalen-7-yl) -4-hydroxyphenyl)acrylic acid (CD3254)

Journal of Medicinal Chemistry

Volumn 56, Issue 21, 2013, Pages 8432-8454

  Jurutka, Peter W ^a   Kaneko, Ichiro ^a   Yang, Joanna ^a   Bhogal, Jaskaran S ^a   Swierski, Johnathon C ^a   Tabacaru, Christa R ^a   Montano, Luis A ^a   Huynh, Chanh C ^a   Jama, Rabia A ^a   Mahelona, Ryan D ^a   Sarnowski, Joseph T ^a   Marcus, Lisa M ^a   Quezada, Alexis ^a   Lemming, Brittney ^a   Tedesco, Maria A ^a   Fischer, Audra J ^a   Mohamed, Said A ^a   Ziller, Joseph W ^b   Ma, Ning ^c   Gray, Geoffrey M ^c   Van Der Vaart, Arjan ^c   Marshall, Pamela A ^a   Wagner, Carl E ^a   more..

^a ARIZONA STATE UNIVERSITY   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

^c UNIVERSITY OF SOUTH FLORIDA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

(4 CYANOPHENYL)N METHOXY N METHYLFORMAMIDE; 1 (6 BROMO 3,4 DIHYDRO 1,1,4,4,7 PENTAMETHYLNAPHTHALEN 2 (1H)YLIDENE) 2 TOSYLHYDRAZINE; 2 [1 (3,5,5,8,8 PENTAMETHYL 5,6,7,8 TETRAHYDRONAPHTHALEN 2 YL)CYCLOPROPYL]PYRIMIDINE 2 CARBOXYLIC ACID; 3 BROMO 4-METHYLBENZALDEHYDE; 3,4 DIHYDRO 1,1,4,4,7 PENTAMETHYLNAPHTHALEN 2 (1H)ONE; 4 [(3,5,5,8,8 PENTAMETHYL 2-5,8 DIHYDRONAPHTHYL)CARBONYL]BENZENECARBONITRILE; 4 [(3,5,5,8,8 PENTAMETHYL 2-5,8 DIHYDRONAPHTHYL)CARBONYL]BENZOIC ACID; 4 [1 (3,5,5,8,8 PENTAMETHYL 2 5,8 DIHYDRONAPHTHYL)VINYL]BENZOIC ACID; 5 (METHOXYCARBONYL)PYRIDINE 2 CARBOXYLIC ACID; 5 (METHOXYCARBONYL)PYRIMIDINE 2 CARBOXYLIC ACID; 5,6,7,8 TETRAHYDRO 3,5,5,8,8 PENTAMETHYLNAPHTHALEN 2 YL 2 BORONIC ACID; 6 [1 (3,5,5,8,8 PENTAMETHYL 5,6,7,8 TETRAHYDRONAPHTHALEN 2 YL)CYCLOPROPYL]NICOTINIC ACID; 6 BROMO 1,1,4,4,7 PENTAMETHYL 1,4 DIHYDRONAPHTHALENE; 6 BROMO 1,2,3,4 TETRAHYDRO 1,1,4,4,7 PENTAMETHYLNAPHTHALENE; 6 BROMO 3,4 DIHYDRO 1,1,4,4,7 PENTAMETHYLNAPHTHALEN 2 (1H)ONE; BEXAROTENE; CD 3254; CHEMICALS AND DRUGS; DIMETHYL PYRIMIDINE 2,5 DICARBOXYLATE; METHYL 2 [(3,5,5,8,8 PENTAMETHYL 5,6,7,8 TETRAHYDRONAPHTHALEN 2 YL)CARBONYL]PYRIMIDINE 5 CARBOXYLATE; METHYL 2 [(3,5,5,8,8 PENTAMETHYL 5,6,7,8 TETRAHYDRONAPHTHALEN 2 YL)ETHENYL]PYRIMIDINE 5 CARBOXYLATE; METHYL 2 [(3,5,8,8 PENTAMETHYL 5,6,7,8 TETRAHYDRONAPHTHALEN 2 YL)CYCLOPROPYL]PYRIMIDINE 5 CARBOXYLATE; METHYL 2 [1 (1,2,3,4 TETRAHYDRO 1,1,4,4,6 PENTAMETHYLNAPHTHALEN 7 YL)VINYL]PYRIDINE 5 CARBOXYLATE; METHYL 6 [(3,5,5,8,8 PENTAMETHYL 5,6,7,8 TETRAHYDRONAPHTHALEN 2 YL)CARBONYL]NICOTINATE; METHYL 6 [(3,5,5,8,8 PENTAMETHYL 5,6,7,8 TETRAHYDRONAPHTHALEN 2 YL)ETHENYL]NICOTINATE; METHYL 6 [(3,5,8,8 PENTAMETHYL 5.6,7, -TETRAHYDRONAPHTHALEN 2 YL)CYCLOPROPYL]NICOTINATE; METHYL 6 [1 (1,2,3,4 TETRAHYDRO 1,1,4,4,6 PENTAMETHYLNAPHTHALEN 7 YL)VINYL]PYRIDINE 3 CARBOXYLATE; RETINOID DERIVATIVE; RETINOID X RECEPTOR; UNCLASSIFIED DRUG; UNINDEXED DRUG;

APOPTOSIS; ARTICLE; BIOLOGICAL ACTIVITY; CONTROLLED STUDY; CUTANEOUS T CELL LYMPHOMA; DRUG DESIGN; DRUG RECEPTOR BINDING; DRUG SYNTHESIS;

COUMARIC ACIDS; CRYSTALLOGRAPHY, X-RAY; DOSE-RESPONSE RELATIONSHIP, DRUG; HUMANS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; RETINOID X RECEPTORS; STRUCTURE-ACTIVITY RELATIONSHIP; TETRAHYDRONAPHTHALENES;

EID: 84887928768     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm4008517     Document Type: Article

References (74)

1. Mangelsdorf, D. J.; Umesono, K.; Evans, R. M. The Retinoid Receptors. In The Retinoids; Academic Press: Orlando, FL, 1994; pp 319-349.
2. Leid, M.; Kastner, P.; Chambon, P. Multiplicity Generates Diversity in the Retinoic Acid Signaling Pathways Trends Biochem. Sci. 1992, 17, 427-433
3. Olefsky, J. M. Nuclear Receptor Minireview Series J. Biol. Chem. 2001, 276, 36863-36864
4. Forman, B. M.; Yang, C.-R.; Au, M.; Casanova, J.; Ghysdael, J.; Samuels, H. H. A domain containing leucine-zipper-like motifs mediates novel in vitro interactions between the thyroid hormone and retinoic acid receptors Mol. Endocrinol. 1989, 3, 1610-1626
5. Mangelsdorf, D. J.; Evans, R. M. The RXR heterodimers and orphan receptors Cell 1995, 83, 841-850
6. Thompson, P. D.; Remus, L. S.; Hsieh, J.-C.; Jurutka, P. W.; Whitfield, G. K.; Galligan, M. A.; Encinas Dominguez, C.; Haussler, C. A.; Haussler, M. R. Distinct retinoid X receptor activation function-2 residues mediate transactivation in homodimeric and vitamin D receptor heterodimeric contexts J. Mol. Endocrinol. 2001, 27, 211-227
7. 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 LXRα and RXRβ ligand-binding domains in a fully agonistic conformation EMBO J. 2003, 22, 4625-4633
8. Nahoum, V.; Perez, E.; Germain, P.; Rodriquez-Barrios, F.; Manzo, F.; Kammerer, S.; Lemaire, G.; Hirsch, O.; Royer, C. A.; Gronemeyer, H.; de Lera, A. R.; Bourguet, W. Modulators of the structural dynamics of the retinoid X receptor to reveal receptor function Proc. Natl. Acad. Sci. U. S. A. 2007, 104, 17323-17328
9. Forman, B. M.; Umesono, K.; Chen, J.; Evans, R. M. Unique response pathways are established by allosteric interactions among nuclear hormone receptors Cell 1995, 81, 541-550
10. Lala, D. S.; Mukherjee, R.; Schulman, I. G.; Canan Koch, S. S.; Dardashti, L. J.; Nadzan, A. M.; Croston, G. E.; Evans, R. M.; Heyman, R. A. Activation of specific RXR heterodimers by an antagonist of RXR homodimers Nature 1996, 383, 450-453
11. Lemon, B. D.; Freedman, L. P. Selective effects of ligands on vitamin D3 receptor- and retinoid X receptor-mediated gene activation in vivo Mol. Cell. Biol. 1996, 16, 1006-1016
12. MacDonald, P. N.; Dowd, D. R.; Nakajima, S.; Galligan, M. A.; Reeder, M. C.; Haussler, C. A.; Ozato, K.; Haussler, M. R. Retinoid X receptors stimulate and 9- cis retinoic acid inhibits 1,25-dihydroxyvitamin D3-activated expression of the rat osteocalcin gene Mol. Cell. Biol. 1993, 13, 5907-5917
13. Thompson, P. D.; Jurutka, P. W.; Haussler, C. A.; Whitfield, G. K.; Haussler, M. R. Heterodimeric DNA binding by the vitamin D receptor and retinoid X receptors is enhanced by 1,25-dihydroxyvitamin D3 and inhibited by 9- cis retinoic acid: evidence for allosteric receptor interactions J. Biol. Chem. 1998, 273, 8483-8491
14. Lehmann, J. M.; Zhang, X. K.; Graupner, G.; Lee, M. O.; Hermann, T.; Hoffmann, B.; Pfahl, M. Formation of Retinoid X Receptor Homodimers Leads to Repression of T3 Response: Hormonal Cross Talk by Ligand-Induced Squelching Mol. Cell. Biol. 1993, 13, 7698-7707
15. Raval-Pandya, M.; Freedman, L. P.; Li, H.; Christakos, S. Thyroid Hormone Receptor Does Not Heterodimerize with the Vitamin D Receptor but Represses Vitamin D Receptor-Mediated Transactivation Mol. Endocrinol. 1998, 12, 1367-1379
16. Thompson, P. D.; Hsieh, J.-C.; Whitfield, G. K.; Haussler, C. A.; Jurutka, P. W.; Galligan, M. A.; Tillman, J. B.; Spindler, S. R.; Haussler, M. R. Vitamin D receptor displays DNA binding and transactivation as a heterodimer with the retinoid X receptor, but not with the thyroid hormone receptor J. Cell. Biochem. 1999, 75, 462-480
17. Yen, P. M.; Liu, Y.; Sugawara, A.; Chin, W. W. Vitamin D Receptors Repress Basal Transcription and Exert Dominant Negative Activity on Triiodothyronine-Mediated Transcriptional Activity J. Biol. Chem. 1996, 271, 10910-10916
18. Altucci, L.; Leibowitz, M. D.; Ogilvie, K. M.; de Lera, A. R.; Gronemeyer, H. RAR and RXR modulation in cancer and metabolic disease Nature Rev. Drug Discovery 2007, 6, 793-810
19. Lehmann, J. M.; Jong, L.; Fanjul, A.; Cameron, J. F.; Lu, X.-P.; Haefner, P.; Dawson, M. I.; Pfahl, M. Retinoids selective for retinoid X receptor pathways Science 1992, 258, 1944-1946
20. Jong, L.; Lehmann, J. M.; Hobbs, P. D.; Harlev, E.; Huffman, J. C.; Pfahl, M.; Dawson, M. I. Conformational effects on retinoid receptor selectivity. 1. Effect of 9-double bond geometry on retinoid X receptor activity J. Med. Chem. 1993, 36, 2605-2613
21. Dawson, M. I.; Jong, L.; Hobbs, P. D.; Cameron, J. F.; Chao, W.-R.; Pfahl, M.; Lee, M.-O.; Shroot, B.; Pfahl, M. Conformational Effects on Retinoid Receptor Selectivity. 2. Effects of Retinoid Bridging Group on Retinoid X Receptor Activity and Selectivity J. Med. Chem. 1995, 38, 3368-3383
22. Boehm, M. F.; Zhang, L.; Badea, B. A.; White, S. K.; Mais, D. E.; Berger, E.; Suto, C. M.; Goldman, M. E.; Heyman, R. A. Synthesis and Structure-Activity Relationships of Novel Retinoid X Receptor-Selective Retinoids J. Med. Chem. 1994, 37, 2930-2941
23. Daiss, J. O.; Burschka, C.; Mills, J. S.; Montana, J. G.; Showell, G. A.; Fleming, I.; Gaudon, C.; Ivanova, D.; Gronemeyer, H.; Tacke, R. Synthesis, Crystal Structure Analysis, and Pharmacological Characterization of Disila-bexarotene, a Disila-Analogue of the RXR-Selective Retinoid Agonist Bexarotene Organometallics 2005, 24, 3192-3199
24. γ heterodimer in colon cancer Cancer Lett. 2006, 240, 225-233
25. Yen, W. -C.; Prudente, R. Y.; Lamph, W. W. Synergistic effect of a retinoid X receptor-selective ligand bexarotene (LGD1069, Targretin) and paclitaxel (Taxol) in mammary carcinoma Breast Cancer Res. Treat. 2004, 88, 141-148
26. Yen, W.-C.; Corpuz, M. R.; Prudente, R. Y.; Cooke, T. A.; Bissonnette, R. P.; Negro-Vilar, A.; Lamph, W. W. A Selective Retinoid X Receptor Agonist Bexarotene (Targretin) Prevents and Overcomes Acquired Paclitaxel (Taxol) Resistance in Human Non-Small Cell Lung Cancer Clin. Cancer Res. 2004, 10, 8656-8664
27. Dragnev, K. H.; Petty, W. J.; Shah, S. J.; Lewis, L. D.; Black, C. C.; Memoli, V.; Nugent, W. C.; Hermann, T.; Negro-Vilar, A.; Rigas, J. R.; Dmitrovsky, E. A Proof-of-Principle Clinical Trial of Bexarotene in Patients with Non-Small Cell Lung Cancer Clin. Cancer Res. 2007, 13, 1794-1800
28. Mukherjee, R.; Davies, P. J. A.; Crombie, D. L.; Bischoff, E. D.; Cesario, R. M.; Jow, L.; Hamanns, L. G.; Boehm, M. F.; Mondon, C. E.; Nadzan, A. M.; Paterniti, J. R.; Heyman, R. A. Sensitization of diabetic and obese mice to insulin by retinoid X receptor agonists Nature 1997, 386, 407-410
29. Sherman, S. I.; Gopal, J.; Haugen, B. R.; Chiu, A. C.; Whaley, K.; Nowlakha, P.; Duvic, M. Central hypothyroidism associated with retinoid X receptor-selective ligands N. Engl. J. Med. 1999, 340, 1075-1079
30. Li, D.; Li, T.; Wang, F.; Tian, H.; Samuels, H. H. Functional Evidence for Retinoid X Receptor (RXR) as a Nonsilent Partner in the Thyroid Hormone Receptor/RXR Heterodimer Mol. Cell. Biol. 2002, 22, 5782-5792
31. Murthy, S.; Born, E.; Mathur, S. N.; Field, F. J. LXR/RXR activation enhances basolateral efflux of cholesterol in CaCo-2 cells J. Lipid Res. 2002, 43, 1054-1064
32. Field, F. J.; Born, E.; Mathur, S. N. LXR/RXR ligand activation enhances basolateral efflux of beta-sitosterol in CaCo-2 cells J. Lipid Res. 2004, 45, 905-913
33. Thacher, S. M.; Standeven, A. M.; Athanikar, J.; Kopper, S.; Castilleja, O.; Escobar, M.; Beard, R. L.; Chandraratna, R. A. S. Receptor Specificity of Retinoid-Induced Epidermal Hyperplasia: Effect of RXR-Selective Agonists and Correlation with Topical Irritation JPET 1997, 282, 528-534
34. Cramer, P. E.; Cirrito, J. R.; Wesson, D. W.; Lee, C. Y. D.; Karlo, J. C.; Zinn, A. E.; Casali, B. T.; Restivo, J. L.; Goebel, D. A.; James, M. J.; Brunden, K. R.; Wilson, D. A.; Landreth, G. E. ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models Science 2012, 335, 1503-1506
35. Landreth, G. E.; Cramer, P. E.; Lakner, M. M.; Cirrito, J. R.; Wesson, D. W.; Brunden, K. R.; Wilson, D. A. Response to Comments on 'ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models.' Science 2013, 340, 924
36. Vuligonda, V.; Thacher, S. M.; Chandraratna, R. A. S. Enantioselective Synthesis of Potent Retinoid X Receptor Ligands: Differential Biological Activities of Individual Antipodes J. Med. Chem. 2001, 44, 2298-2303
37. Farmer, L. J.; Marron, K. S.; Canan Koch, S. S.; Hwang, C. K.; Kallel, E. A.; Zhi, L.; Nadzan, A. M.; Robertson, D. W.; Bennani, Y. L. Aza-retinoids as novel retinoid X receptor-specific agonists Bioorg. Med. Chem. Lett. 2006, 16, 2352-2356
38. Kagechika, H.; Kawachi, E.; Hashimoto, Y.; Himi, T.; Shudo, K. Retinobenzoic Acids. 1. Structure-Activity Relationships of Aromatic Amides with Retinoidal Activity J. Med. Chem. 1988, 31, 2182-2192
39. Michellys, P. Y.; Ardecky, R. J.; Chen, J. H.; Crombie, D. L.; Etgen, G. J.; Faul, M. M.; Faulkner, A. L.; Grese, T. A.; Heyman, R. A.; Karanewsky, D. S.; Klausing, K.; Leibowitz, M. D.; Liu, S.; Mais, D. A.; Mapes, C. M.; Marschke, K. B.; Reifel-Miller, A.; Ogilvie, K. M.; Rungta, D.; Thompson, A. W.; Tyhonas, J. S.; Boehm, M. F. Novel (2 E,4 E,6 Z)-7-(2-Alkoxy-3,5- dialkylbenzene)-3-methylocta-2,4,6-trienoic Acid Retinoid X Receptor Modulators are Active in Models of Type 2 Diabetes J. Med. Chem. 2003, 46, 2683-2696
40. Michellys, P.-Y.; Ardecky, R. J.; Chen, J.-H.; D'Arrigo, J.; Grese, T. A.; Karanewsky, D. S.; Leibowitz, M. D.; Liu, S.; Mais, D. A.; Mapes, C. M.; Montrose-Rafizadeh, C.; Ogilvie, K. M.; Reifel-Miller, A.; Rungta, D.; Thompson, A. W.; Tyhonas, J. S.; Boehm, M. F. Design, Synthesis, and Structure-Activity Relationship Studies of Novel 6,7-Locked-[7-(2-alkoxy-3,5-dialkylbenzene)-3- methylocta]-2,4,6-trienoic Acids J. Med. Chem. 2003, 46, 4087-4103
41. Michellys, P.-Y.; Darrigo, J.; Grese, T. A.; Karanewsky, D. S.; Leibowitz, M. D.; Mais, D. A.; Mapes, C. M.; Reifel-Miller, A.; Rungta, D.; Boehm, M. F. Design, synthesis and structure-activity relationship of novel RXR-selective modulators Bioorg. Med. Chem. Lett. 2004, 14, 1593-1598
42. Wagner, C. E.; Jurutka, P. W.; Marshall, P. A.; Groy, T. L.; van der Vaart, A.; Ziller, J. W.; Furmick, J. K.; Graeber, M. E.; Matro, E.; Miguel, B. V.; Tran, I. T.; Kwon, J.; Tedeschi, J. N.; Moosavi, S.; Danishyar, A.; Philp, J. S.; Khamees, R. O.; Jackson, J. N.; Grupe, D. K.; Badshah, S. L.; Hart, J. W. Modeling, Synthesis and Biological Evaluation of Potential Retinoid X Receptor (RXR) Selective Agonists: Novel Analogues of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7, 8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) J. Med. Chem. 2009, 52, 5950-5966
43. Furmick, J. K.; Kaneko, I.; Walsh, A. N.; Yang, J.; Bhogal, J. S.; Gray, G. M.; Baso, J. C.; Browder, D. O.; Prentic, J. L. S.; Montano, L. A.; Huynh, C. C.; Marcus, L. M.; Tsosie, D. G.; Kwon, J. S.; Quezada, A.; Reyes, N. M.; Lemming, B.; Saini, P.; van der Vaart, A.; Groy, T. L.; Marshall, P. A.; Jurutka, P. W.; Wagner, C. E. Modeling, Synthesis and Biological Evaluation of Potential Retinoid X Receptor-Selective Agonists: Novel Halogenated Analogues of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) ChemMedChem 2012, 7, 1551-1566
44. Boehm, M. F.; Zhang, L.; Zhi, L.; McClurg, M. R.; Berger, E.; Wagoner, M.; Mais, D. E.; Suto, C. M.; Davies, P. J. A.; Heyman, R. A.; Nadzan, A. M. Design and Synthesis of Potent Retinoid X Receptor Selective Ligands That Induce Apoptosis in Leukemia Cells J. Med. Chem. 1995, 38, 3146-3155
45. Zhang, L.; Badea, B. A.; Enyeart, D.; Berger, E. M.; Mais, D. E.; Boehm, M. F. Synthesis of Isotopically Labeled 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8- tetrahydro-2-naphthyl)ethenyl]benzoic Acid (LGD1069) J. Labelled Compd. Radiopharm. 1995, 36, 701-712
46. Faul, M. M.; Ratz, A. M.; Sullivan, K. A.; Trankle, W. G.; Winneroski, L. L. Synthesis of Novel Retinoid X Receptor-Selective Retinoids J. Org. Chem. 2001, 66, 5772-5782
47. Santin, E. P.; Germain, P.; Quillard, F.; Khanwalkar, H.; Rodriguez-Barrios, F.; Gronemeyer, H.; de Lera, A. R.; Bourguet, W. Modulating Retinoid X Receptor with a Series of (E)-3-[4-Hydroxy-3-(3-alkoxy-5,5,8,8- tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)phenyl]acrylic Acids and Their 4-Alkoxy Isomers J. Med. Chem. 2009, 52, 3150-3158
48. Gianni, M.; Ponzanelli, I.; Mologni, L.; Reichert, U.; Rambaldi, A.; Terao, M.; Garattini, E. Retinoid-dependent growth inhibition, differentiation and apoptosis in acute promyelocytic leukemia cells. Expression and activation of caspases Cell Death Differ. 2000, 7, 447-460
49. Shapiro, R. H.; Heath, M. J.; Tosylhydrazones, V. Reaction of Tosylhydrazones with Alkyllithium Reagents. A New Olefin Synthesis J. Am. Chem. Soc. 1967, 89, 5734-5735
50. Shapiro, R. H.; Lipton, M. F.; Kolonko, K. J.; Buswell, R. L.; Capuano, L. A. Tosylhydrazones and alkyllithium reagents: more on the regiospecificity of the reaction and the trapping of three intermediates Tetrahedron Lett. 1975, 16, 1811-1814
51. Miyaura, N.; Yamada, K.; Suzuki, A. A new stereospecific cross-coupling by the palladium-catalyzed reaction of 1-alkenylboranes with 1-alkenyl or 1-alkynyl halides Tetrahedron Lett. 1979, 20, 3437-3440
52. Adams, N. D.; Adams, J. L.; Burgess, J. L.; Chaudhari, A. M.; Copeland, R. A.; Donatelli, C. A.; Drewry, D. H.; Fisher, K. E.; Hamajima, T.; Hardwicke, M. A.; Huffman, W. F.; Koretke-Brown, K. K.; Lai, Z. V.; McDonald, O. B.; Nakamura, H.; Newlander, K. A.; Oleykowski, C. A.; Parrish, C. A.; Patrick, D. R.; Plant, R.; Sarpong, M. A.; Sasaki, K.; Schmidt, S. J.; Silva, D. J.; Sutton, D.; Tang, J.; Thompson, C. S.; Tummino, P. J.; Wang, J. C.; Xiang, H.; Yang, J.; Dhanak, D. Discovery of GSK1070916, a Potent and Selective Inhibitor of Aurora B/C Kinase J. Med. Chem. 2010, 53, 3973-4001
53. Horner, L.; Hoffmann, H. M. R.; Wippel, H. G. Phosphororganische Verbindungen, XII. Phosphinoxyde als Olefinierungsreagenzien Chem. Ber. 1958, 91, 61-63
54. Wadsworth, W. S., Jr.; Emmons, W. D. The Utility of Phosphonate Carbanions in Olefin Synthesis J. Am. Chem. Soc. 1961, 83, 1733
55. Lalloyer, F.; Pedersen, T. A.; Gross, B.; Lestavel, S.; Yous, S.; Vallez, E.; Gustafsson, J.-A.; Mandrup, S.; Fievet, C.; Staels, B.; Tailleux, A. Rexinoid Bexarotene Modulates Triglyceride but not Cholesterol Metabolism via Gene-Specific Permissivity of the RXR/LXR Heterodimer in the Liver Arterioscler. Thromb. Vasc. Biol. 2009, 29, 1488-1495
56. Wan, Y.-J. Y.; An, D.; Cai, Y.; Repa, J. J.; Chen, T. H.-P.; Flores, M.; Postic, C.; Magnuson, M. A.; Chen, J.; Chien, K. R.; French, S.; Mangelsdorf, D. J.; Sucov, H. M. Hepatocyte-Specific Mutation Establishes Retinoid X Receptor α as a Heterodimeric Integrator of Multiple Physiological Processes in the Liver Mol. Cell. Biol. 2000, 20, 4436-4444
57. van der Leede, B.-j. M.; van den Brink, C. E.; van der Saag, P. T. Retinoic Acid Receptor and Retinoid X Receptor Expression in Retinoic Acid-Resistant Human Tumor Cell Lines Mol. Carcinog. 1993, 8, 112-122
58. Zhang, C.; Hazarika, P.; Ni, X.; Weidner, D. A.; Duvic, M. Induction of Apoptosis by Bexarotene in Cutaneous T-Cell Lymphoma Cells Clin. Cancer Res. 2002, 8, 1234-1240
59. Budihardjo, I.; Holt, O.; Lutter, M.; Luo, X.; Wang, X. Biochemical Pathways of Caspase Activation During Apoptosis Annu. Rev. Cell Dev. Biol. 1999, 15, 269-290
60. Kotani, H.; Tanabe, H.; Mizukami, H.; Amagaya, S.; Inoue, M. A Naturally Occurring Rexinoid, Honokiol, Can Serve as a Regulator of Various Retinoid X Receptor Heterodimers Biol. Pharm. Bull. 2012, 35, 1-9
61. Zou, A.; Elgort, M. G.; Allegretto, E. A. Retinoid X receptor (RXR) ligands activate the human 25-hydroxyvitamin D3-24-hydroxylase promoter via RXR heterodimer binding to two vitamin D-responsive elements and elicit additive effects with 1,25-dihydroxyvitamin D3 J. Biol. Chem. 1997, 272, 19027-19034
62. Hallenbeck, P. L.; Phyillaier, M.; Nikodem, V. M. Divergent effects of 9- cis -retinoic acid receptor on positive and negative thyroid hormone receptor-dependent gene expression J. Biol. Chem. 1993, 268, 3825-3828
63. Hong-Qi, Y.; Zhi-Kun, S.; Sheng-Di, C. Current advances in the treatment of Alzheimer's disease: focus on considerations targeting Aβ and tau Transl. Neurodegener. 2012, 1, 21
64. Gross, M. Understanding amyloid and Alzheimer's disease Curr. Biol. 2012, R381-R384
65. Appleby, B. S.; Nacopoulos, D.; Milano, N.; Zhong, K.; Cummings, J. L. A Review: Treatment of Alzheimer's Disease Discovered in Repurposed Agents Dementia Geriatr. Cognit. Disord. 2013, 35, 1-22
66. Mangelsdorf, D. J.; Umesono, K.; Kliewer, S. A.; Borgmeyer, U.; Ong, E. S.; Evans, R. M. A direct repeat in the cellular retinol-binding protein type II gene confers differential regulation by RXR and RAR Cell 1991, 66, 555-561
67. Forman, B. M.; Umesono, K.; Chen, J.; Evans, R. M. Unique response pathways are established by allosteric interactions among nuclear hormone receptors Cell 1995, 81, 541-550
68. Zimmerman, F. K. Procedures used in the induction of mitotic recombination and mutation in the yeast Saccharomyces cerevisiae Mutat. Res. 1975, 31, 71-86
69. Zimmermann, F. K.; Kern, R.; Rasenberger, H. A yeast strain for simultaneous detection of mitotic crossing over, mitotic gene conversion, and reverse mutation Mutat. Res. 1975, 28, 381-388
70. Marshall, P. A. Using Saccharomyces cerevisiae to Test the Mutagenicity of Household Compounds: An Open Ended Hypothesis-Driven Teaching Lab CBE-Life Sci. Educ. 2007, 6, 307-315
71. Egea, P. F.; Mitschler, A.; Moras, D. Molecular Recognition of Agonist Ligands by RXRs Mol. Endocrinol. 2002, 16, 987-997
72. Love, J. D.; Gooch, J. T.; Benko, S.; Li, C.; Nagy, L.; Chatterjee, V. K. K.; Evans, R. M.; Schwabe, J. W. R. The Structural Basis for the Specificity of Retinoid-X Receptor-selective Agonists: New Insights Into the Role of Helix H12 J. Biol. Chem. 2002, 277, 11385-11391
73. Morris, G. M.; Huey, R.; Lindstrom, W.; Sanner, M. F.; Belew, R. K.; Goodsell, D. S.; Olson, A. J. AutoDock4 and AutoDock Tools4: automated docking with selective receptor flexibility J. Comput. Chem. 2009, 30, 2785-2791
74. O'Boyle, N. M.; Banck, M.; James, C. A.; Morley, C.; Vandermeersch, T.; Hutchison, G. R. Open Babel: an open chemical toolbox J. Cheminf. 2011, 3, 33