Medicinal chemistry of hERG optimizations: Highlights and hang-ups

Journal of Medicinal Chemistry

Volumn 49, Issue 17, 2006, Pages 5029-5046

  Jamieson, Craig ^a   Moir, Elizabeth M ^a   Rankovic, Zoran ^a   Wishart, Grant ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMPHOLYTE; PHOSPHODIESTERASE IV; POTASSIUM CHANNEL HERG;

ALPHA CHAIN; CHEMICAL ANALYSIS; COMPUTER MODEL; ELECTROPHYSIOLOGY; HEART ARRHYTHMIA; HEART MUSCLE POTENTIAL; POTASSIUM CURRENT; QT PROLONGATION; REVIEW; STRUCTURE ACTIVITY RELATION;

ANIMALS; BINDING SITES; CHEMISTRY, PHARMACEUTICAL; ETHER-A-GO-GO POTASSIUM CHANNELS; HUMANS; MOLECULAR STRUCTURE; POTASSIUM CHANNEL BLOCKERS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 33747505446     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm060379l     Document Type: Review

References (71)

1. Abbott, G. W.; Sesti, F.; Splawski, I.; Buck, M. E.; Lehmann, M. H.; Timothy, K. W.; Keating, M. T.; Goldstein, S. A. MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell 1999, 97, 175-187.
2. Fermini, B.; Fossa, A. A. The impact of drug-induced QT interval prolongation on drug discovery and development. Nat. Rev. Drug Discovery 2003, 2, 439-447.
3. Keating, M. T.; Sanguinetti, M. C. Molecular and cellular mechanisms of cardiac arrhythmias. Cell 2001, 104, 569-580.
4. + channel. A model for bad behavior. J. Med. Chem. 2003, 46, 2017-2022.
5. 3H]Dofetilide binding to HERG transfected membranes: a potential high throughput preclinical screen. Eur. J. Pharmacol. 2001, 430, 147-148.
6. Product is commercially available from Molecular Devices Inc. http://www.moleculardevices.com/pages/instruments/patchxpress.html (accessed March 20, 2006).
7. Valentin, J.-P.; Hoffmann, P.; De Clerck, F.; Hammond, T. G.; Hondeghem, L. Review of the predictive value of the Langendorff heart model (Screenit system) in assessing the proarrhythmic potential of drugs. J. Pharmacol. Toxicol. Methods 2004, 49, 171-181.
8. Gintant, G. A.; Limberis, J. T.; McDermott, J. S.; Wegner, C. D.; Cox, B. F. The canine Purkinje fiber: an in vitro model system for acquired long QT syndrome and drug-induced arrhythmogenesis. J. Cardiovasc. Pharmacol. 2001, 37, 607-618.
9. Carlsson, L. In vitro and in vivo models for testing arrhythmogenesis in drugs. J. Intern. Med. 2006, 259, 70-80.
10. Yamamoto, K.; Tamura, T.; Imai, R.; Yamamoto, M. Acute canine model for drug-induced torsades de pointes in drug safety evaluation. Influences of anesthesia and validation with quinidine and astemizole. Toxicol. Sci. 2001, 60. 165-176.
11. 1 antihistamines on animal models of QTc prolongation. Drug Safety 1999, 21, 39-44.
12. Vaz, R. J.; Li, Y.; Rampe, D. Human ether-a-go-go related gene (HERG): a chemist's perspective. Prog. Med. Chem. 2005, 43, 1-18.
13. Aronov, A. M. Predictive in silico modeling for hERG channel blockers. Drug Discovery Today 2005, 10, 149-155.
14. + channel blockade: current knowledge and strategies for the early prediction during drug development. Med. Res. Rev. 2005, 25, 133-166.
15. Mitcheson, J. S.; Chen, J.; Lin, M.; Culberson, C.; Sanguinetti, M. C. A structural basis for drug-induced long QT syndrome. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 12329-12333.
16. Fernandez, D.; Ghanta, A.; Kauffman, G. W.; Sanguinetti, M. C. Physicochemical features of the hERG channel drug binding site. J. Biol. Chem. 2004, 279, 10120-10127.
17. Mitcheson, J. S.; Perry, M. D. Molecular determinants of high-affinity drug binding to HERG channels. Curr. Opin. Drug Discovery Dev. 2003, 6, 667-674.
18. Ishii, K.; Kondo, K.; Takahashi, M.; Kimura, M.; Endoh, M. An amino acid residue whose change by mutation affects drug binding to the HERG channel. FEBS Lett. 2001, 506, 191-195.
19. + Channel Block. J. Biol. Chem. 2002, 277, 23587-23595.
20. Perry, M.; de Groot, M. J.; Helliwell, R.; Leishman. D.; Tristani-Firouzi, M.; Sanguinetti, M. C.; Mitcheson, J. Structural determinants of HERG channel block by clofilium and ibutilide. Mol. Pharmacol. 2004, 66, 240-249.
21. Witchel, H. J.; Dempsey, C. E.; Sessions, R. B.; Perry, M.; Milnes, J. T.; Hancox, J. C.; Mitcheson, J. S. The low-potency, voltage-dependent HERG blocker propafenone. Molecular determinants and drug trapping. Mol. Pharmacol. 2004, 66, 1201-1212.
22. Sanguinetti, M. C.; Mitcheson, J. S. Predicting drug-hERG channel interactions that cause acquired long QT syndrome. Trends Pharmacol. Sci. 2005, 26, 119-124.
23. Pearlstein, R. A.; Vaz, R. J.; Kang, J.; Chen, X.-L.; Preobrazhenskaya, M.; Shchekotikhin, A. E.; Korolev, A. M.; Lysenkova, L. N.; Miroshnikova, O. V.; Hendrix, J.; Rampe, D. Characterization of HERG potassium channel inhibition using CoMSiA 3D QSAR and homology modeling approaches. Bioorg. Med. Chem. Lett. 2003, 13, 1829-1835.
24. + channel: application to ligand binding. Bioorg. Med. Chem. Lett. 2005, 15, 1737-1741.
25. + channel using docking and molecular dynamics methods. FEBS Lett. 2005, 579, 2939-2944.
26. Wood, A.; Armour, D. The discovery of the CCR5 receptor antagonist, UK-427,857, a new agent for the treatment of HIV infection and AIDS. Prog. Med. Chem. 2005, 43, 239-271.
27. + channel blockers. J. Med. Chem. 2002, 45, 3844-3853.
28. Ekins, S.; Crumb, W. J.; Sarazan, R. D.; Wikel, J. H.; Wrighton, S. A. Three-dimensional quantitative structure-activity relationship for inhibition of human ether-a-go-go-related gene potassium channel. J. Pharmacol. Exp. Ther. 2002, 301, 427-434.
29. Kr potassium channel blockers: novel class II1 antiarrhythmic agents. Bioorg. Med. Chem. Lett. 2004, 14, 4771-4777.
30. Cianchetta, G.; Li, Y.; Kang, J.; Rampe, D.; Fravolini, A.; Cruciani, G.; Vaz, R. J. Predictive models for hERG potassium channel blockers. Bioorg. Med. Chem. Lett. 2005, 15, 3637-3642.
31. Keser̈, G. M. Prediction of hERG potassium channel affinity by traditional and hologram QSAR methods. Bioorg. Med. Chem. Lett. 2003, 13, 2773-2775.
32. Bains, W.; Basman, A.; White, C. HERG binding specificity and binding site structure: evidence from a fragment-based evolutionary computing SAR study. Prog. Biophys. Mol. Biol. 2004, 86, 205-233.
33. Song, M.; Clark, M. Development and evaluation of an in silico model for hERG binding. J. Chem. Inf. Model. 2006, 46, 392-300.
34. Zolotoy, A. B.; Plouvier, B. P.; Beatch, G. B.; Hayes, E. S.; Wall, R. A.; Walker, M. J. A. Physicochemical determinants for drug induced blockade of HERG potassium channels: effect of charge and charge shielding. Curr. Med. Chem.: Cardiovasc. Hematol. Agents 2003, 1, 225-241.
35. Roche, O.; Trube, G.; Zuegge, J.; Pflimlin, P.; Alanine, A.; Schneider, G. A virtual screening method for prediction of the hERG potassium channel liability of compound libraries. ChemBioChem 2002, 3, 455-459.
36. O'Brien, S. E.; de Groot, M. J. Greater than the sum of its parts: combining models for useful ADMET prediction. J. Med. Chem. 2005, 48, 1287-1291.
37. Tobita, M.; Nishikawa, T.; Nagashima, R. A discriminant model constructed by the support vector machine method for HERG potassium channel inhibitors. Bioorg. Med. Chem. Lett. 2005, 15, 2886-2890.
38. Buyck, C.; Tollenaere, J.; Engels, M.; De Clerck, F. An in silico model for detecting potential hERG blocking. Presented at the 14th European Symposium on Quantitative Structure-Activity Relationships, Bournemouth, U.K., September 8-13, 2002.
39. + blocking potency: application of structural knowledge. SAR QSAR Environ. Res. 2004, 15, 399-411.
40. + channel blockers. Bioorg. Med. Chem. 2004, 12, 2307-2315.
41. Stouch, T. R.; Kenyon, J. R.; Johnson, S. R.; Chen, X.-Q.; Doweyko, A.; Li, Y. In silico ADME/Tox: why models fail. J. Comput.-Aided Mol. Des. 2003, 17, 83-92.
42. a values were calculated with the following: ACD PhysChem Batch, version 4.76; Advanced Chemistry Development, Inc.: Toronto, Ontario, Canada.
43. Bell, I. M.; Gallicchio, S. N.; Abrams, M.; Beshore, D. C.; Buser, C. A.; Culberson, J. C.; Davide, J.; Ellis-Hutchings, N.; Fernandes, C.; Gibbs, J. B.; Graham, S. L.; Hartman, G. D.; Heimbrook, D. C.; Homnick, C. F.; Huff, J. R.; Hassahun, K.; Koblan, K. S.; Kohl, N. E.; Lobell, R. B.; Lynch, J. J.; Miller, P. A.; Omer, C. A.; Rodrigues, A. D.; Walsh, E. S.; Williams, T. M. Design and biological activity of (S)-4-(5-{[1-(3-chlorobenzyl)-2-oxopyrrolidin-3-ylamino] methyl}-imidazol-1-ylmethyl)benzonitrile, a 3-aminopyrrolidinone farnesyl-transferase inhibitor with excellent cell potency. J. Med. Chem. 2001, 44, 2933-2949.
44. Bell, I. M.; Gallicchio, S. N.; Abrams, M.; Beese, L. S.; Beshore, D. C.; Bhimnathwala, H.; Bogusky, M. J.; Buser, C. A.; Culberson, J. C.; Davide, J.; Ellis-Hutchings, N.; Fernandes, C.; Gibbs, J. B.; Graham, S. L.; Hamilton, K. A.; Hartman, G. D.; Heimbrook, D. C.; Homnick, C. F.; Huber, H.; Huff, J. R.; Hassahun, K.; Koblan, K. S.; Kohl, N. E.; Lobell, R. B.; Lynch, J. J.; Robinson, R.; Rodrigues, A. D.; Taylor, J. S.; Walsh, E. S.; Williams, T. M.; Zartman, C. B. 3-Aminopyrrolidinone farnesyltransferase inhibitors: design of macrocyclic compounds with improved pharmacokinetics and excellent cell potency. J. Med. Chem. 2002, 45, 2388-2409.
45. Blum, C. A.; Zheng, X.; De Lombaert, S. Design, synthesis, and biological evaluation of substituted 2-cyclohexyl-4-phenyl-1H-imidazoles: potent and selective neuropeptide Y Y5-receptor antagonists. J. Med. Chem. 2004, 47, 2318-2325.
46. McCauley, J. A.; Theberge, C. R.; Romano, J. J.; Billings, S. B.; Anderson, K. D.; Claremon, D. A.; Freidinger, R. M.; Bednar, R. A.; Mosser, S. D.; Gaul, S. L.; Connolly, T. M.; Condra, C. L.; Xia, M.; Cunningham, M. E.; Bednar, B.; Stump, G. L.; Lynch, J. J.; Macaulay, A.; Wafford, K. A.; Koblan, K. S.; Liverton, N. J. NR2B-selective N-methyl-D-aspartate antagonists: synthesis and evaluation of 5-substituted benzimidazoles. J. Med. Chem. 2004, 47, 2089-2096.
47. Kim, D.; Wang, L.; Hale, J. J.; Lynch, C. L.; Budhu, R. J.; MacCoss, M.; Mills, S. G.; Malkowitz, L.; Gould, S. L.; Demartino, J. A.; Springer, M. S.; Hazuda, D.; Miller, M.; Kessler, J.; Hrin, R. C.; Carver, G.; Carella, A.; Henry, K.; Lineberger, J.; Schleif, W. A.; Emini, E. A. Potent 1,3,4-trisubstituted pyrrolidine CCR5 receptor antagonists: effects of fused heterocycles on antiviral activity and pharmacokinetic properties. Bioorg. Med. Chem. Lett. 2005, 15, 2129-2134.
48. Shu, M.; Loebach, J. L.; Parker, K. A.; Mills, S. G.; Chapman, K. T.; Shen, D. M.; Malkowitz, L.; Gould, S. L.; DeMartino, J. A.; Siciliano, S. J.; DiSalvo, J.; Lyons, K.; Pivnichny, J. V.; Kwei, G. Y.; Carella, A.; Carver, G.; Holmes, K.; Schleif, W. A.; Danezeisen, R.; Hazuda, D.; Kessler, J.; Lineberger, J.; Miller, M. D.; Emini, E. A. Antagonists of the human CCR5 receptor containing 4-(pyrazolyl)-piperidine side chains. Part 3: SAR studies on the benzylpyrazole segment. Bioorg. Med. Chem. Lett. 2004, 14, 947-952.
49. KS. Bioorg. Med. Chem. Lett. 2004, 14, 99-102.
50. + channel HERG. Mol Pharmacol. 2001, 59, 122-126.
51. 4 receptor with improved selectivity over ion channels. Bioorg. Med. Chem. 1998, 6, 743-753.
52. 2A receptor antagonists. J. Med. Chem. 2001, 44, 1603-1614.
53. 2A ligands for the treatment of insomnia. Bioorg. Med. Chem. Lett. 2005, 15, 3665-3669.
54. Woosley, R. L. Cardiac actions of antihistamines. Annu. Rev. Pharmacol. Toxicol. 1996, 36, 233-252.
55. Rampe, D.; Wibble, B.; Brown, A. M.; Dage, R. C. Effects of terfenadine and its metabolites on a delayed rectifier K+ channel cloned from human heart. Mol. Pharmacol. 1993, 44, 1240-1245.
56. Xu, J.; Mathvink, R.; He, J.; Park, Y. J.; He, H.; Leiting, B.; Lyons, K. A.; Marsilio, F.; Patel, R. A.; Wu, J. K.; Thornberry, N. A.; Weber, A. E. Discovery of potent and selective phenylalanine based dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. Lett. 2005, 15, 2533-2536.
57. Edmonson, S. D.; Mastracchio, A.; Beconi, M.; Colwell, L. F.; Habulihaz, B.; He, H.; Kumar, S.; Leitin, B.; Lyons, K. A.; Mao, A.; Marsilio, F.; Patel, R. A.; Wu, J. K.; Zhu, L.; Thornberry, N. A.; Weber, A. E.; Parmee, E. R. Potent and selective proline derived dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. Lett. 2004, 14, 5151-5155.
58. Edmondson, S. D.; Mastracchio, A.; Duffy, J.; Eiermann, G. J.; He, H.; Ita, I.; Leiting, B.; Leone, J. F.; Lyons, K. A.; Makarewicz, A. M.; Patel, R. A.; Petrov, A.; Wu, J. K.; Thornberry, N. A.; Weber, A. E. Discovery of potent and selective orally bioavailable β-substituted phenylalanine derived dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. Lett. 2005, 15, 3048-3052.
59. Vaz, R. J.; Gao, Z.; Pribish, J.; Chen, X.; Levell, J.; Davis, L.; Albert, E.; Brollo, M.; Ugolini, A.; Cramer, D. M.; Cairns, J.; Sides, K.; Liu, F.; Kwong, J.; Kang, J.; Rebello, S.; Elliot, M.; Lim, H.; Chellaraj, V.; Singleton, R. W.; Li, Y. Design of bivalent ligands using hydrogen bond linkers: synthesis and evaluation of inhibitors for human β-tryptase. Bioorg. Med. Chem. Lett. 2004, 14, 6053-6056.
60. Fraley, M. E.; Arrington, K. L.; Buser, C. A.; Cieko, P. A.; Coll, K. E.; Fernandes, C.; Hartman, G. D.; Hoffman, W. F.; Lynch, J. J.; McFall, R. C.; Rickert, K.; Singh, R.; Smith, S.; Thomas, K. A.; Wong, B. K. Optimization of the indolyl quinoline class of KDR (VEGFR-2) kinase inhibitors: effects of 5-amido- and 5-sulphonamido-indolyl groups on pharmacokinetics and hERG binding. Bioorg. Med. Chem. Lett. 2004, 14, 351-355.
61. 2A receptor antagonists. J. Med. Chem. 2002, 45, 492-503.
62. 1 receptor antagonists II. Bioorg. Med. Chem. Lett. 2002, 12, 1759-1762.
63. Friesen, R. W.; Ducharme, Y.; Ball, R. G.; Blouin, M.; Boulet, L.; Côté, B.; Frenette, R.; Girard, M.; Guay, D.; Huang, Z.; Jones, T. R.; Laliberté, F.; Lynch, J. J.; Mancini, J.; Martins, E.; Masson, P.; Muise, E.; Pon, D. J.; Siegl, P. K. S.; Styhler, A.; Tsou, N. N.; Turner, M. J.; Young, R. N.; Girard, Y. Optimization of a tertiary alcohol series of phosphodiesterase-4 (PDE4) Inhibitors: structure-activity relationship related to PDE4 inhibition and human ether-a-go-go related gene potassium channel binding affinity. J. Med. Chem. 2003, 46, 2413-2426.
64. Bilodeau, M. T.; Balitza, A. E.; Koester, T. J.; Manley, P. J.; Rodman L. D.; Buser-Doepner, C.; Coll, K. E.; Fernandes, C.; Gibbs, J. B. Heimbrook, D. C.; Huckle, W. R.; Kohl, N.; Lynch, J. J.; Mao, X. McFall, R. C.; McLoughlin, D.; Miller-Stein, C.; Rickert, K. W. Sepp-Lorenzino, L.; Shipman, J. M.; Subramanian, R.; Thomas, K. A.; Wong, B. K.; Yu, S.; Hartman, G. D. Potent N-(1,3-thiazoyl-2-yl)pyridine-2-amine vascular endothelial growth factor receptor tyrosine kinase inhibitors with excellent pharmacokinetics and low affinity for the hERG ion channel. J. Med. Chem. 2004, 47, 6363-6372.
65. 2A antagonists: The successful reduction of hERG activity. Part 2. Bioorg. Med. Chem. Lett. 2005, 15, 3675-3678.
66. Zhang, H. C.; Derian, C. K.; McComsey, D. F.; White, K. B.; Ye, H.; Hecker, L. R.; Li, J.; Addo, M. F.; Groll, D.; Eckardt, A. J.; Smith, C. E.; Li, Q.; Cheung, W. M.; Conway, B. R.; Emanuel, S.; Demarest, B. P.; Maryanoff, B. E. Novel Indolylindazolylmaleimides as inhibitors of protein kinase C-β: synthesis, biological activity and cardiovascular safety. J. Med. Chem. 2005, 48, 1725-1728.
67. 4 receptor. Bioorg. Med. Chem. 1998, 6, 1731-1743.
68. Liang, J.; Brochu, R. M.; Cohen, C. J.; Dick, I. E.; Felix, J. P.; Fisher, M. H.; Garcia, M. L.; Kaczorowski, G. J.; Lyons, K. A.; Meinke, P. T.; Priest, B. T.; Schmalhofer, W. A.; Smith, M. M.; Tarpley, J. W.; Williams, B. S.; Martin, W. J.; Parsons, W. H. Discovery of potent and use dependent sodium channel blockers for the treatment of chronic pain. Bioorg. Med. Chem. Lett. 2005, 15, 2943-2947.
69. + channel. Science 2005, 309, 897-903.
70. Kang, J.; Reynolds, W. P.; Chen, X. L.; Ji, J.; Wang, H.; Rampe, D. E. Mechanisms underlying the QT interval-prolonging effects of sevoflurane and its interactions with other QT-prolonging drugs. Anesthesiology 2006, 104, 1015-1022.
71. Kuryshev, Y. A.; Picker, E.; Wang, L.; Hawryluk, P.; Dennis, A. T.; Wible B. A.; Brown, A. M.; Kang, J.; Chen, X. L.; Sawamura, K.; Reynolds, W.; Rampe, D. Pentamidine-induced long QT syndrome and block of HERG trafficking. J. Pharmacol. Exp. Ther. 2005, 312, 316-323.