A new class of blockers of the voltage-gated potassium channel Kv1.3 via modification of the 4- or 7-position of khellinone

Journal of Medicinal Chemistry

Volumn 49, Issue 4, 2006, Pages 1433-1441

  Harvey, Andrew J ^a   Baell, Jonathan B ^a   Toovey, Nathan ^a   Homerick, Daniel ^b   Wulff, Heike ^b  

^a WALTER AND ELIZA HALL INSTITUTE OF MEDICAL RESEARCH   (Australia)

^b UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

5 ACETYL 4 (4' CHLORO)BENZYLOXY 6 HYDROXY 7 METHOXYBENZOFURAN; 5 ACETYL 7 (4' BROMO)BENZYLOXY 6 HYDROXY 4 METHOXYBENZOFURAN; BENZOFURAN DERIVATIVE; BENZYL DERIVATIVE; CHALCONE DERIVATIVE; DIMER; KHELLINONE; KHELLINONE DERIVATIVE; NATURAL PRODUCT; POTASSIUM CHANNEL BLOCKING AGENT; POTASSIUM CHANNEL HERG; POTASSIUM CHANNEL KV1.3; UNCLASSIFIED DRUG; VOLTAGE GATED POTASSIUM CHANNEL; VOLTAGE GATED POTASSIUM CHANNEL KV1.3 BLOCKER;

ANIMAL CELL; ARTICLE; AUTOIMMUNE DISEASE; CONCENTRATION RESPONSE; DRUG EFFECT; DRUG POTENCY; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; EFFECTOR CELL; HUMAN; HUMAN CELL; LEUKEMIA CELL LINE; LYMPHOCYTE PROLIFERATION; MEMORY T LYMPHOCYTE; MOUSE; NONHUMAN; NORMAL HUMAN; REACTION ANALYSIS; STRUCTURE ANALYSIS;

BENZOFURANS; CELL LINE; CELL PROLIFERATION; HUMANS; IMMUNOSUPPRESSIVE AGENTS; KV1.3 POTASSIUM CHANNEL; PATCH-CLAMP TECHNIQUES; POTASSIUM CHANNEL BLOCKERS; STRUCTURE-ACTIVITY RELATIONSHIP; T-LYMPHOCYTES;

EID: 33144478897     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm050839v     Document Type: Article

References (46)

1. Lin, C. S.; Boltz, R. C.; Blake, J. T.; Nguyen, M.; Talento, A. et al. Voltage-gated Potassium Channels Regulate Calcium-dependent Pathways Involved in Human T Lymphocyte Activation. J. Exp. Med. 1993, 177, 637-645.
2. Lewis, R. S.; Cahalan, M. D. Potassium and Calcium Channels in Lymphocytes. Annu. Rev. Immunol. 1995, 13, 623-653.
3. Cahalan, M. D.; Wulff, H.; Chandy, K. G. Molecular Properties and Physiological Roles of Ion Channels in the Immune System. J. Clin. Immunol. 2001, 21, 235-252.
4. Chandy, K. G.; Wulff, H.; Beeton, C.; Pennington, M.; Gutman, G. A. et al. Potassium Channels as Targets for Specific Immunomodulation. Trends Pharmacol Sci. 2004, 25, 280-289.
5. Lewis, R. S. Calcium Signaling Mechanisms in T lymphocytes. Annu. Rev. Immunol. 2001, 19, 497-521.
6. Hess, S. D.; Oortgiesen, M.; Cahalan, M. D. Calcium Oscillations in Human T and Natural Killer Cells depend on Membrane Potential and Calcium Influx. J. Immunol. 1993, 150, 2620-2633.
7. + Channel in Effector Memory T cells as New Target for MS. J. Clin. Invest. 2003, 111, 1703-1713.
8. + Channel Expression During B-cell Differentiation: Implications for Immunomodulation and Autoimmunity. J. Immunol. 2004, 173, 776-786.
9. Beeton, C.; Chandy, K. G. Potassium Channels, Memory T cells and Multiple Sclerosis. Neuroscientist 2005, in press.
10. + Channels Improves Experimental Autoimmune Encephalomyelitis and Inhibits T Cell Activation. J. Immunol. 2001, 166, 936-944.
11. + Channels Ameliorates Experimental Autoimmune Encephalomyelitis, a Model for Multiple Sclerosis. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 13942-13947.
12. Beeton, C.; Pennington, M. W.; Wulff, H.; Singh, S.; Nugent, D. et al. Targeting Effector Memory T cells with a Selective Peptide Inhibitor of Kv1.3 Channels for Therapy of Autoimmune Diseases. Mol. Pharmacol. 2005, 67, 1369-1381.
13. Rus, H.; Pardo, C. A.; Hu, L.; Darrah, E.; Cudrici, C. et al. The Voltage-Gated Potassium Channel Kv1.3 is Highly Expressed on Inflammatory Infiltrates in Multiple Sclerosis Brain. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 11094-11099.
14. Norton, R. S.; Pennington, M. W.; Wulff, H. Potassium Channel Blockade by the Sea Anemone Toxin ShK for the Treatment of Multiple Sclerosis and Other Autoimmune Diseases. Curr. Med. Chem. 2004, 11, 3041-3052.
15. Wulff, H.; Beeton, C.; Chandy, K. G. Potassium Channels as Therapeutic Targets for Autoimmune Disorders. Curr. Opin. Drug Discovery Dev. 2003, 6, 640-647.
16. + Channel gene. Proc. Natl. Acad. Sci. U.S.A. 1990, 87, 9411-9415.
17. Baell, J. B.; Harvey, A. J.; Norton, R. S. Design and Synthesis of Type-III Mimetics of ShK Toxin. J. Comput.-Aided Mol. Des. 2002, 16, 245-262.
18. Harvey, A. J.; Gable, R. W.; Baell, J. B. A Three-Residue, Continuous Binding Epitope Peptidomimetic of ShK Toxin as a Kv1.3 Inhibitor. Bioorg. Med. Chem. Lett. 2005, 15, 3193-3196.
19. Felix, J. P.; Bugianesi, R. M.; Schmalhofer, W. A.; Borris, R.; Goetz, M. A. et al. Identification and Biochemical Characterization of a Novel Nortriterpene Inhibitor of the Human Lymphocyte Voltage-Gated Potassium Channel, Kv1.3. Biochemistry 1999, 38, 4922-4930.
20. Ghanshani, S.; Wulff, H.; Miller, M. J.; Rohm, H.; Neben, A. et al. Up-regulation of the IKCal Potassium Channel During T-cell Activation: Molecular Mechanism and Functional Consequences. J. Biol. Chem. 2000, 275, 37137-37149.
21. Koo, G. C.; Blake, J. T.; Shah, K.; Staruch, M. J.; Dumont, F. et al. Correolide and Derivatives are Novel Immunosuppressants Blocking the Lymphocyte Kv1.3 Potassium Channels. Cell. Immunol. 1999, 197, 99-107.
22. Hanner, M.; Schmalhofer, W. A.; Green, B.; Bordallo, C.; Liu, J. et al. Binding of Correolide to Kv1 Family Potassium Channels. J. Biol. Chem. 1999, 274, 25237-25244.
23. Schmalhofer, W. A.; Bao, J.; McManus, O. B.; Green, B.; Matyskiela, M. et al. Identification of a New Class of Inhibitors of the Voltage-Gated Potassium Channel, Kv1.3, with Immunosuppressant Properties. Biochemistry 2002, 18, 7781-7794.
24. Vennekamp, J.; Wulff, H.; Beeton, C.; Calabresi, P. A.; Grissmer, S. et al. Kv1.3 Blocking 5-Phenylalkoxypsoralens: a New Class of Immunomodulators. Mol. Pharmacol. 2004, 65, 1364-1373.
25. Baell, J. B.; Gable, R. W.; Harvey, A. J.; Toovey, N.; Herzog, T. et al. Khellinone Derivatives as Blockers of the Voltage-Gated Potassium Channel Kv1.3: Synthesis and Immunosuppressive Activity. J. Med. Chem. 2004, 47, 2326-2336.
26. Abu-Shady, H.; Soine, T. O. Experiments with Khellin. I. The Preparation of Desmethylkhellin and Some of its Derivatives. J. Am. Pharm. Assoc. 1952, 41, 325-327.
27. Gammill, R. B. Preparing 7-Alkoxybenzofurans, Intermediates Used Therein, and Furochromones used Therefrom. Eur. Pat. Appl. EP 94769, 1983, p 18.
28. Schonberg, A.; Sina, A. On Visnagin and Khellin and Related Compounds - a Simple Synthesis of Chromone. J. Am. Chem. Soc. 1950, 72, 3396-3399.
29. Renato, S.; DiPaco, G. Ann. Chim. (Rome) 1958, 48, 1205-1209.
30. Fourneau, J. P. Ann. Pharm. Fr. 1953, 11, 685-695.
31. Baell, J. B.; Gable, R. W.; Harvey, A. J. 1,6-Bis(5-acetyl-4,7- dimethoxybenzofuran-6-yloxy)hexane. Acta Crystallogr. Sect. E 2004, 60, O996-O997.
32. Bennett, P. B.; Guthrie, H. R. Trends in Ion Channel Drug Discovery. Advances in Screening Technologies. Trends Biotechnol. 2003, 21, 563-569.
33. Wang, X.; Li, M. Automated Electrophysiology: High Throughput of Art. Assay Drug Dev. Technol. 2003, 1, 695-708.
34. Levy, D. I.; Deutsch, C. Recovery from C-Type Inactivation is Modulated by Extracellular Potassium. Biophys. J. 1996, 70, 798-805.
35. Cahalan, M. D.; Chandy, K. G.; DeCoursey, T. E.; Gupta, S. A Voltage-Gated Potassium Channel in Human T Lymphocytes. J. Physiol. (London) 1985, 358, 197-237.
36. + Channel Occurs by a Cooperative Mechanism. Biophys. J. 1995, 69, 896-903.
37. + Channel Block by Verapamil and Related Compounds in Rat Alveolar Epithelial Cells. J. Gen. Physiol. 1995, 106, 745-779.
38. + Channel mKv1.3 by the Phenylalkylamine Verapamil: Kinetic Aspects of Block and Disruption of Accumulation of Block by a Single Point Mutation. Br. J. Pharmacol. 2000, 131, 1275-1284.
39. Still, W. C.; Kahn, M.; Mitra, A. Rapid Chromatographic Technique for Preparative Separations With Moderate Resolution. J. Org. Chem. 1978, 43, 2923-2925.
40. Murti, V. V. S.; Seshadri, T. R. Nuclear Oxidation in Flavones and Related Compounds. XXIII. A Synthesis of Khellin. Proc. Ind. Acad. Sci. Sect. A 1949, 30A, 107-113.
41. Asker, W.; Shalaby, A.; Zayed, S. Reactions with Mercaptans 0.5. Action of Aromatic Thiols on Furocoumarins, Furochromones, and 2-Aralkylidene-3(2H)- Thianaphthenone-1,1-Dioxides. J. Org. Chem. 1958, 23, 1781-1783.
42. Musante, C.; Stener, A. Gazz. Chim. Ital. 1956, 86, 297-315.
43. Martin, M.; Cautain, M.; Sado, M.; Zuckerka, F.; Fourneau, J. P. et al. Synthesis and Beta-Adrenolytic Properties of Some Amino alcohols of Fluoro 3,2-G Chromone. Eur. J. Med. Chem. 1974, 9, 563-570.
44. Grissmer, S.; Nguyen, A. N.; Aiyar, J.; Hanson, D. C.; Mather, R. J. et al. Pharmacological Characterization of Five Cloned Voltage-Gated K+ Channels, Types Kv1.1, 1.2, 1.3, 1.5, and 3.1, Stably Expressed in Mammalian Cell Lines. Mol. Pharmacol. 1994, 45, 1227-1234.
45. + Channel, IKCal: A Potential Immunosuppressant. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 8151-8156.
46. Bardien-Kruger, S.; Wulff, H.; Arieff, Z.; Brink, P.; Chandy, K. G. et al. Characterization of the Human Voltage-Gated Potassium Channel Gene, KCNA7, a Candidate Gene For Inherited Cardiac Disorders, and its Exclusion as a Cause of Progressive Familial Heart Block 1 (PFHBI). Eur. J. Human Gen. 2002, 10, 36-43.