Inhibition of sphingosine 1-phosphate lyase for the treatment of rheumatoid arthritis: Discovery of (E)-1-(4-((1 R,2 S,3 R)-1,2,3,4-tetrahydroxybutyl)-1 H -imidazol-2-yl)ethanone oxime (LX2931) and (1 R,2 S,3 R)-1-(2-(Isoxazol-3-yl)-1 H -imidazol-4-yl)butane-1,2,3,4-tetraol (LX2932)

Journal of Medicinal Chemistry

Volumn 53, Issue 24, 2010, Pages 8650-8662

  Bagdanoff, Jeffrey T ^a   Donoviel, Michael S ^a   Nouraldeen, Amr ^a   Carlsen, Marianne ^a   Jessop, Theodore C ^a   Tarver, James ^a   Aleem, Saadat ^a   Dong, Li ^a   Zhang, Haiming ^a   Boteju, Lakmal ^a   Hazelwood, Jill ^a   Yan, Jack ^a   Bednarz, Mark ^a   Layek, Suman ^a   Owusu, Iris B ^a   Gopinathan, Suma ^a   Moran, Liam ^a   Lai, Zhong ^a   Kramer, Jeff ^a   Kimball, S David ^a   Yalamanchili, Padmaja ^a   Heydorn, William E ^a   Frazier, Kenny S ^a   Brooks, Barbara ^a   Brown, Philip ^a   Wilson, Alan ^a   Sonnenburg, William K ^a   Main, Alan ^a   Carson, Kenneth G ^a   Oravecz, Tamas ^a   Augeri, David J ^a   more..

^a LEXICON PHARMACEUTICALS INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 [2 (ISOXAZOL 3 YL) 1H IMIDAZOL 4 YL]BUTANE 1,2,3,4 TETRAOL; 1 [4 (1,2,3,4 TETRAHYDROXYBUTYL) 1H IMIDAZOL 2 YL]ETHANONE OXIME; ANTIRHEUMATIC AGENT; LX 2931; LX 2932; LYASE; SPHINGOSINE 1 PHOSPHATE LYASE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; DISTRIBUTION VOLUME; DOSE RESPONSE; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG DOSE ESCALATION; DRUG HALF LIFE; DRUG SYNTHESIS; DRUG TARGETING; DRUG TOLERABILITY; HUMAN; IN VIVO STUDY; LYMPHOCYTE COUNT; MALE; MOUSE; NONHUMAN; PHENOTYPE; RAT; RHEUMATOID ARTHRITIS; RODENT; STRUCTURE ACTIVITY RELATION;

ALDEHYDE-LYASES; ANIMALS; ANTIRHEUMATIC AGENTS; ARTHRITIS, EXPERIMENTAL; BLOOD PRESSURE; CELL MOVEMENT; DOGS; HEART RATE; IMIDAZOLES; ISOXAZOLES; LYMPHOCYTES; MACACA FASCICULARIS; MALE; MICE; MICE, INBRED C57BL; MICE, INBRED DBA; OXIMES; RATS; RATS, SPRAGUE-DAWLEY; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 78650381368     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm101183p     Document Type: Article

References (67)

1. Vogel, P.; Donoviel, M. S.; Read, R.; Hansen, G. M.; Hazelwood, J.; Anderson, S. J.; Sun, W.; Swaffield, J.; Oravecz, T. Incomplete Inhibition of Sphingosine 1-Phosphate Lyase Modulates Immune System Function yet Prevents Early Lethality and Non-Lymphoid Lesions PloS ONE 2009, 4 (1) e4112
2. Fyrst, H.; Saba, J. D. Sphingosine-1-phosphate lyase in development and disease: Sphingosine metabolism takes flight Biochim. Biophys. Acta 2008, 1781, 448-458
3. For a review, see: Kumar, A.; Saba, J. D. Lyase to live by: sphingosine phosphate lyase as a therapeutic target Expert Opin. Ther. Targets 2009, 13, 1-13
4. Weber, C.; Krueger, A.; Münk, A.; Bode, C.; Van Veldhoven, P. P.; Gräler, M. H. Discontinued postnatal thymocyte development in sphingosine 1-phosphate-lyase-deficient mice J. Immunol. 2009, 7, 4292-4301
5. Bektas, M.; Allende, M. L.; Lee, B. G.; Chen, W; Amar, M. J.; Remaley, A. T.; Saba, J. D.; Proia, R. L. Sphingosine 1-phosphate lyase deficiency disrupts lipid homeostatis in liver J. Biol. Chem. 2010, 10880-10889
6. Reiss, U.; Oskouian, B.; Zhou, J.; Gupta, V.; Sooriyakumaran, P.; Kelly, S.; Wang, E.; Merrill, A. H.; Saba, J. D. Sphingosine-phosphate lyase enhances stress-induced ceramide generation and apoptosis J. Biol. Chem. 2004, 279, 1281-1290
7. Moore, A. N.; Kampfl, A. W.; Zhao, X.; Hayes, R. L.; Dash, P. K. Sphingosine 1-phosphate induces apoptosis of cultured hippocampal neurons that requires protein phosphatases and activator protein-1 complexes Neuroscience 1999, 94, 405-415
8. Maceyka, M. H.; Sankala, N. C.; Hait, H.; Le Stunff, H.; Liu, R.; Toman, C.; Collier, M.; Zhang, L. S.; Satin, A. H.; Merrill, S.; Milstien, S.; Spiegel, S. SphK1 and SphK2, sphingosine kinase isoenzymes with opposing functions in sphingolipid metabolism J. Biol. Chem. 2005, 280, 37118-37129
9. Pyne, S.; Pyne, N. J. Sphingosine 1-phosphate signalling in mammalian cells J. Biochem. 2000, 349, 385-402
10. McVerry, B.; Garcia, J. In vitro and in vivo modulation of vascular barrier integrity by sphingosine 1-phosphate: mechanistic insights Cell. Signalling 2005, 131-139
11. Cyster, J. G. Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs Annu. Rev. Immunol. 2005, 23, 127-159
12. Hait, N. C.; Oskeritzian, C. A.; Paugh, S. W.; Milstien, S.; Spiegel, S. Sphingosine kinases, sphingosine 1-phosphate, apoptosis and diseases Biochim. Biophys. Acta 2006, 1758, 2016-2026
13. Rosen, H.; Goetzl, E. J. Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network Nature Rev. Immunol. 2005, 5, 560-570
14. Saba, J. D.; Hla, T. Point-counterpoint of sphingosine 1-phosphate metabolism Circ. Res. 2004, 94, 7240-7234
15. For a general review, see: Marsolais, D.; Rosen, H. Chemical modulators of sphingosine-1-phosphate receptors as barrier oriented therapeutic molecules Nature Rev. Drug Discovery 2009, 8, 297-307
16. Goetzl, E. J.; Wang, W.; McGiffert, C.; Huang, M.-C.; Graeler, M. H. Sphingosine 1-phosphate and its G protein-coupled receptors constitute a multifunctional immunoregulatory system J. Cell. Biochem. 2004, 92, 1104-1114
17. Sanchez, T; Hla, T. Structural and functional characteristics of S1P receptors J. Cell. Biochem. 2004, 92, 913-922
18. Goetzl, E. J.; Liao, J.-J.; Huang, M.-C. Regulation of the roles of sphingosine 1-phosphate and its type 1 G protein-coupled receptor in T cell immunity and autoimmunity Biochem. Biophys Acta 2008, 1781, 503-507
19. Goetzl, E. J.; Rosen, H. Regulation of immunity by lysosphigolipids and their G protein-coupled receptors J. Clin. Invest. 2004, 114, 1531-1537
20. Cohen, J. A.; Barkhof, F.; Comi, G.; Hartung, H.-P.; Khatri, B. O.; Montalban, X.; Pelletier, J.; Capra, R.; Gallo, P.; Izquierdo, G.; Tiel-Wilck, K.; de Vera, A.; Jin, J.; Stites, T.; Wu, S.; Aradhye, S.; Kappos, L. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis N. Engl. J. Med. 2010, 362, 402-415
21. Adachi, K.; Kohara, T.; Nakao, N.; Masafumi, A.; Chiba, K.; Mishina, T.; Sasaki, S.; Fujita, T. Design, Synthesis, and Structure-Activity Relationships of 2-Substituted-2-Amino-1,3-Propanediols: Discovery of a Novel Immunosuppressant, FTY720 Bioorg. Med. Chem. Lett. 1995, 5, 853-856
22. Chi, H.; Flavell, R. A. Cutting Edge: Regulation of T Cell Trafficking and Primary Immune Responses by Sphingosine 1-Phosphate Receptor 1 J. Immunol. 2005, 174, 2485-2488
23. Wang, W.; Huang, M.-C.; Goetzl, E. J. Type 1 Sphingosine 1-Phosphate G Protein-Coupled Receptor (S1P1) Mediation of Enhanced IL-4 Generation by CD4 T cells from S1P1 Transgenic Mice J. Immunol. 2007, 178, 4885-4890
24. For a comprehensive treatment, see: Brinkmann, V. Sphingosine 1-phosphate receptors in health and disease: mechanistic insights from gene deletion studies and reverse pharmacology Pharmacol. Ther. 2007, 115, 84-105
25. Maceyka, M.; Spiegel, S. Sphingosine-1-phosphate receptors Handb. Cell Signaling 2004, 2, 247-251
26. Oo, M. L.; Thangada, S.; Wu, M. T.; Liu, C. H.; Macdonald, T. L.; Lynch, K. R.; Lin, C. Y.; Hla, T. Immunosuppressive and anti-angiogenic sphingosine 1-phosphase receptor-1 agonists unduce ubiquitinylation and proteasomal degredation of the receptor J. Biol. Chem. 2007, 282, 9082-9089
27. Parrill, A. L.; Wang, D.; Bautista, D. L.; Van Brocklyn, J. R.; Lorincz, Z.; Fischer, D. J.; Baker, D. L.; Liliom, K.; Spiegel, S.; Tigyi, G. Identification of edg1 receptor residues that recognize sphingosine 1-phosphate J. Biol. Chem. 2000, 275, 39379-39384
28. LaMontagne, K.; Littlewood-Evans, A.; Schnell, C.; O'Reilly, T.; Wyder, L.; Sanchez, T.; Probst, B.; Butler, J.; Wood, A.; Liau, G.; Billy, E.; Theuer, A.; Hla, T.; Wood, J. Antagonism of sphingosine-1-phosphate receptors by FTY720 inhibits angiogenesis and tumor vascularization Cancer Res. 2006, 66, 221-231
29. Maceyka, M.; Milstein, S.; Spiegel, S. Sphingosine-1-phosphate: the Swiss army knife of sphingolipid signaling J. Lipid Res. 2009, S272-S276
30. Schwab, S. R.; Pereira, J. P.; Matloubian, M.; Xu, Y.; Huang, Y.; Cyster, J. G. Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients Science 2005, 309, 1735-1739
31. Bandhuvula, P.; Fyrst, H.; Saba, J. D. A rapid fluorescence assay for sphingosine-1-phosphate lyase enzyme activity J. Lipid Res. 2007, 48, 2769-2778
32. Bagdanoff, J. T.; Donoviel, M. S.; Nouraldeen, A.; Tarver, J.; Fu, Q; Carlsen, M.; Jessop, T.; Zhang, H.; Hazelwood, H.; Nguyen, H.; Baugh, S. D. P.; Gardyan, M; Terranova, K. M.; Barbosa, J.; Yan, J.; Bednarz, M.; Layek, S.; Taylor, J.; Digeorge-Foushee, A. M.; Gopinathan, S.; Bruce, D.; Smith, T.; Moran, L.; O'Neill, E.; Kramer, J.; Lai, Z.; Kimball, S. D.; Liu, Q.; Sun, W.; Yu, S.; Swaffield, J.; Wilson, A.; Main, A.; Carson, K. G.; Oravecz, T.; Augeri, D. J. Inhibition of Sphingosine-1-Phosphate Lyase (S1PL) for the Treatment of Autoimmune Disorders J. Med. Chem. 2009, 52, 3941-3953
33. Hodge, J. E.; Rist, C. E. Amadori rearrangement under new conditions and its significance for nonenzymatic browning reactions J. Am. Chem. Soc. 1953, 75, 316-322
34. Hodge, J. E.; Fisher, B. E. In Methods in Carbohydrate Chemistry; Whistler, R. L.; Wolfrom, M. L.; Bemiller, J. N., Eds.; Academic Press: New York, 1963; Vol. II, pp 99-103.
35. Buchi, G.; Halweg, K. M. A Convenient Synthesis of 2-Acetyl-4(5)-(1(R), 2(S),3(R),4-tetrahydroxybutyl)-imidazole J. Org. Chem. 1985, 50, 1134-1136
36. 1- 1.
37. Yu, X. Q.; Kramer, J.; Moran, L; O'Neill, E.; Nouraldeen, A.; Oravecz, T.; Wilson, A. Pharmacokinetic and Pharmacodynamic modeling of 2-acetyl-4(5)-tetrahydroxyimidazole-induced peripheral lymphocyte sequestration through increasing lymphoid sphingosine 1-phosphate Xenobiotica 2010, 40, 350-356
38. Kondoh, M.; Yagi, K. Progress in absorption enhancers based on tight junction Expert Opin. Drug Delivery 2007, 4, 275-286
39. Van Veldhoven determined the catalytic turnover of S1PL in mammalian tissues and cultured cells to be between 20 and 100 pmol/min/mg protein. Internal unpublished results with full length protein including N-terminal membrane-binding region normally bound to endoplasmic reticulum supported these findings and further internal study with a fluorogenic substrate, in addition to radioactively-labeled S-1-P, also supported slow catalytic turnover rates for S-1-P Lyase. For references, see: Van Veldhoven, P. P. Sphingosine-1-phosphate Lyase Methods Enzymol. 1999, 311, 244-254
40. Van Veldhoven, P. P.; Mannaerts, G. P. Sphingosine-Phosphate Lyase Adv. Lipid Res. 1993, 26, 69-98 For fluorogenic substrate, see Bedia, C.; Camacho, L.; Casas, J.; Abad, J. L.; Delgado, A.; Van Veldhoven, P. P.; Fabrias, G. Synthesis of a Fluorogenic Analogue of Sphingosine-1-Phosphate and Its Use to Determine Sphingosine-1-Phosphate Lyase Activity ChemBioChem 2009, 10, 820-822
41. Internal findings using FTY-720 as a positive control, unpublished results.
42. Phosphorylation of FTY720 is a facile process and synthetic agonist binds to S1PR on the cell surface of lymphocytes. For related published results, see: Foster, C. A.; Howard, L. M.; Schweitzer, A.; Persohn, E.; Hiestand, P. C.; Balatoni, B.; Reuschel, R.; Beerli, C.; Schwartz, M.; Billich, A. J. Pharmacol. Exp. Ther. 2007, 323, 469-476
43. Queneau, P. The saga of aspirin: centuries-old ancestors of an old lady who doesn't deserve to die Therapie 2001, 56, 723-726
44. Miner, J.; Hoffhines, A. The discovery of aspirin's antithrombotic effects Texas Heart Inst. J. 2007, 34, 179-186
45. Mahdi, J. G.; Mahdi, A. J.; Madhi, A. J.; Bowen, I. D. The historical analysis of aspirin discovery, its relation to the willow tree and antiproliferative and anticancer potential Cell Proliferation 2006, 39, 147-155
46. Bentley, R. The development of penicillin: Genesis of a famous antibiotic Perspect. Biol. Med. 2005, 48, 444-452
47. Diggins, F. W. The true history of the discovery of penicillin, with refutation of the misinformation in the literature Br. J. Biomed. Sci. 1999, 56, 83-93
48. For a general review, see: Masataka, Y. Iodine and Living Body Kagaku Keizai 2008, 55, 75-80
49. Fujita, T.; Yoneta, M.; Hirose, R.; Sasaki, S.; Inoue, K.; Kiuchi, M; Hirase, S.; Adachi, K.; Arita, M.; Chiba, K. Simple compounds, 2-alkyl-2-amino-1,3-propanediols have potent immunosuppressive activity Bioorg. Med. Chem. Lett. 1995, 5, 847-852
50. Adachi, K.; Kohara, T.; Nakao, N.; Masafumi, A.; Chiba, K.; Mishina, T.; Sasaki, S.; Fujita, T. Design, Synthesis, and Structure-Activity Relationships of 2-Substituted-2-Amino-1,3-Propanediols: Discovery of a Novel Immunosuppressant, FTY720 Bioorg. Med. Chem. Lett. 1995, 5, 853-856
51. Kiuchi, M.; Adachi, K.; Kohara, T.; Teshima, K.; Masubuchi, Y.; Mishina, T.; Fujita, T. Synthesis and biological evaluation of 2,2-disubstituted 2-aminoethanols: analogues of FTY720 Bioorg. Med. Chem. Lett. 1998, 8, 101-106
52. Bagli, J. F.; Kluepfel, D. Elucidation of Structure and Stereochemistry of Myriocin. A Novel Antifungal Antibiotic J. Org. Chem. 1973, 38, 1253-1260
53. Bagli, J. F.; Kluepfel, D.; St.-Jacques, M. Edlucidation of Structure and Stereochemistry of Myriocin. A Novel Antifungal Antibiotic J. Org. Chem. 1973, 38, 1253-1260
54. Miyake, Y.; Kozutsumi, Y.; Nakamura, S.; Fujita, T.; Kawasaki, T. Serine palmitoyltransferase is the primary target of a sphingosine-like immunosuppressant, ISP-1/ myriocin Biochem. Biophys. Res. Commun. 1995, 211, 396-403
55. Chen, J. K.; Lane, W. S.; Schreiber, S. L. The identification of myriocin-binding proteins Chem. Biol. 1999, 6, 221-235
56. Brinkmann, V.; Davis, M. D.; Heise, C. E.; Albert, R.; Cottens, S.; Hof, R.; Bruns, C.; Prieschl, E.; Baumruker, T.; Hiestand, P.; Foster, C. A.; Zollinger, M.; Lynch, K. R. The immune modulator FTY720 targets sphingosine 1-phosphate receptors J. Biol. Chem. 2002, 277, 21453-21457
57. Rivera, J.; Proia, R. L.; Olivera, A. The alliance of sphingosine-1-phosphate and its receptors in immunity Nature Rev. Immunol. 2008, 8, 753-763
58. Billich, A.; Baumruker, T.; Sphingolipid Metabolizing Enzymes as Novel Theraputic Targets. In Lipids in Health and Disease; Quinn, P. J.; Wang, X., Eds.; Springer Science Business Media BV: New York, 2008; pp 487-522.
59. Peng, X.; Hassoun, P. M.; Sammani, S.; McVerry, B. J.; Burne, M. J.; Rabb, H.; Pearse, D.; Tuder, R. M.; Garcia, J. G. N. Protective effects of sphingosine 1-phosphate in murine endotoxin-induced inflammatory lung injury Am. J. Respir. Crit. Care Med. 2004, 169, 1245-1251 (Pubitemid 38680403)
60. Nofer, J. R.; van der Giet, M.; Tolle, M.; Wolinska, I.; von Wnuck Lipinski, K.; Baba, H. A.; Tietge, U. J.; Godecke, A.; Ishii, I.; Kleuser, B.; Schafers, F.; Fobker, M; Zidek, W.; Assmann, G.; Chun, J.; Levkau, B. HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3 J. Clin. Invest. 2004, 113, 569-581
61. Van der Giet, M.; Tolle, M.; Kleuser, B. Relevance and potential of sphingosine-1-phosphate in vascular inflammatory disease Biol. Chem. 2008, 389, 1381-1390
62. Hughes, J. E.; Srinivasan, S.; Lynch, K. R.; Proia, R. L.; Ferdek, P.; Hedrick, C. C. Sphingosine-1-phosphate induces an antiinflammatory phenotype in macrophages Circ. Res. 2008, 102, 950-958
63. Rolin, J.; Sand, K. L.; Knudsen, E.; Maghazachi, A. A. FTY720 and SEW2871 reverse the inhibitory effect of S1P on natural killer cell mediated lysis of K562 tumor cells and dendritic cells but not on cytokine release Cancer Immunol. Immunother. 2010, 59, 575-586
64. Augeri, D. J. Inhibition of Sphingosine-1-Phosphate Lyase for the Treatment of Autoimmune Disorders. First Disclosure of LX2931/LX2932. 239th ACS National Meeting, San Francisco, CA, March 21-25, 2010, MEDI-36.
65. Fleischmann, R.; Frazier, K.; Freiman, J.; Brooks, B.; Donoviel, M.; Oravecz, T.; Augeri, D.; Heydorn, W.; Kelly, M.; Brown, P. Co-Administration of the Oral S1P-Lyase Inhibitor LX2931 with Methotrexate was Well Tolerated Over 14 Days in Patients with Stable Rheumatoid Arthritis. Meeting of the American College of Rheumatology, Philadelphia, PA, October 18, 2009, abstract 426.
66. See experimental section of: Salojin, K.; Owusu, R. B.; Millerchip, K. A.; Potter, M.; Platt, K. A.; Oravecz, T. Essential Role of MAPK Phosphatase-1 in the Negative Control of Innate Immune Responses J. Immunol. 2006, 176, 1899-1907
67. 3) δ ppm 160.92, 138.92, 109.81, 107.24.