Discovery and synthesis of tetrahydroindolone derived semicarbazones as selective Kv1.5 blockers

Bioorganic and Medicinal Chemistry Letters

Volumn 16, Issue 22, 2006, Pages 5859-5863

  Wu, Shengde ^a   Fluxe, Andrew ^a   Janusz, John M ^a   Sheffer, James B ^a   Browning, Greg ^a   Blass, Benjamin ^a   Cobum, Keith ^a   Hedges, Richard ^a   Murawsky, Michael ^a   Fang, Bin ^a   Fadayel, Gina M ^a   Hare, Michelle ^a   Djandjighian, Laurent ^a  

^a PROCTER AND GAMBLE PHARMACEUTICALS   (United States)

Author keywords

Atrial antiarrhythmic; In vivo efficacy; Kv1.5 Inhibitor; Semicarbazone

Indexed keywords

CALCIUM CHANNEL L TYPE; POTASSIUM CHANNEL; POTASSIUM CHANNEL BLOCKING AGENT; SEMICARBAZONE DERIVATIVE;

ANESTHESIA; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; DRUG ACTIVITY; DRUG POTENCY; DRUG STRUCTURE; HEART LEFT VENTRICLE; HEART MUSCLE REFRACTORY PERIOD; HEART RIGHT ATRIUM; NONHUMAN; STRUCTURE ACTIVITY RELATION;

ANIMALS; CALCIUM CHANNELS, L-TYPE; ETHER-A-GO-GO POTASSIUM CHANNELS; EVOKED POTENTIALS, MOTOR; HEART RATE; HUMANS; KV1.5 POTASSIUM CHANNEL; NEUROPSYCHOLOGICAL TESTS; POTASSIUM CHANNEL BLOCKERS; SEMICARBAZONES; STRUCTURE-ACTIVITY RELATIONSHIP; SWINE;

SUS SCROFA;

EID: 33749238378     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2006.08.057     Document Type: Article

References (26)

1. Kannel W.B., Wolf P.A., Benjamin E.J., and Levy D. Am. J. Cardiol 82 (1998) 2N
2. Pratt C.M., and Moye L.A. Am. J. Cardiol 65 (1990) 20B
3. Waldo A.L., Camm A.J., DeRuyter H., Friedman P.L., MacNeil D.J., Pauls J.F., Pitt B., Pratt C.M., Schwartz P.J., and Veltri E.P. Lancet 348 (1996) 7
4. Tomaselli G. Heart Drug 1 (2001) 183
5. Wang Z., Fermini B., and Nattel S. Circ. Res 73 (1993) 1061
6. Feng J., Wible B., Li G.R., Wang Z., and Nattel S. Circ. Res. 80 (1997) 572
7. Purerfellner H. Curr. Med. Chem. CV and H Agents 2 (2004) 79
8. Lynch, J. Jr.; Swanson, R. J.; Fermini, B. U.S. Patent 5969017, 1999; PCT Int. Appl. 1998, WO 98/18475.
9. Lynch, J. Jr.; Swanson, R. J.; Fermini, B. U.S. Patent 5935945, 1999; PCT Int. Appl. 1998, WO 98/18476.
10. Stump G.L., Wallace A.A., Regan C.P., and Lynch Jr. J.J. J. Pharmacol. Exp. Ther. 315 (2005) 1362
11. Castle, N. A.; Hughes, P. F.; Mendoza, J. S.; Wilson, J. W.; Amato, G.; Beaudoin, S.; Gross, M.; McNaughton-smith, G. U.S. Patent 6083986, 2000; PCT Int. Appl. 1997, WO 98/04521.
12. Gross, M.; Castle, N. A. PCT Int. Appl. 1999, WO 99/37607.
13. Gross, M.; Beaudoin, S.; Reed, A. D. U.S. Patent 6458794 B2, 2002; PCT Int. Appl. 2001, WO 01/46155 A1.
14. Castle, N. A.; Gross, M.; Mendoza, J. S.; U.S. Patent 6174908 B1, 2001; U.S. Patent, 6395730 B1, 2002; PCT Int. Appl. 1999, WO 99/62891.
15. Peukert, S.; Brendel, J.; Hemmerle, H.; Kleemann, H-W. PCT Int. Appl. (2002), WO 02/48131 A1. WO 02/44137 A1. WO 02/446162 A1.
16. Peukert S., Brendel J., Pirard B., Bruggemann A., Below P., Kleemann H.-W., Hemmerle H., and Schmidt W. J. Med. Chem 46 (2003) 486
17. Brendel, J.; Schmidt, W.; Below, P. PCT Int. Appl. 2001, WO 01/25189.
18. Brendel, J., Pirard, B. U.S. Patent 0193422 A1, 2002.
19. Brendel, J.; Bohme, T.; Peukert, S.; Kleemann, H.-W. U.S. Patent 0114499 A1, 2003.
20. Wirth K.J., Paehler T., Rosenstein B., Knobloch K., Maier T., Frenzel J., Brendel J., Busch A.E., and Bleich M. Cardiovasc.Res. 60 (2003) 298
21. Peukert S., Brendel J., Pirard B., Strubing C., Kleemann H.-W., Bohme T., and Hemmerle H. Bioorg. Med. Chem. Lett. 14 (2004) 2823
22. Wu, S.; Janusz, J. 227th ACS National Meeting, Anaheim, CA. March 28, 2004.
23. 50 estimating were done using Graphpad software (Ver. 4).
24. 50 estimating were done using Graphpad software (Ver. 4).
25. 2 37 °C incubator. All final solutions contain the anion exchange inhibitor, probenecid (2.5 mM). The 96-well plates are then placed in the center position of the FLIPR 1(Fluorometric Imaging Plate Reader, Molecular Devices Corporation). Cell monolayers in each well are simultaneously illuminated at 488 nm with an Argon ion laser, and fluorescence emission is monitored using a 510-570 nm bandpass filter and a cooled CCD camera. To depolarize the plasma membrane and activate L-type calcium channels, 50μL per well of 20 mM KCl (final concentration) is dispensed simultaneously to all 96 wells using the FLIPR's automatic 96-well pipettor. Fluorescence measurements are captured for 5 min. following KCl addition. Calcium influx, expressed as % control, is calculated for each concentration of test compound and concentration-response curves and IC50 values are generated using GraphPad Prism 4.0.
26. Hamill, et al. Pflugers Archiv. 391 (1981) 85