Pyrazolopyridazine alpha-2-delta-1 ligands for the treatment of neuropathic pain

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 15, 2010, Pages 4683-4688

  Myatt, James W ^a   Healy, Mark P ^a   Bravi, Gianpaolo S ^a   Billinton, Andrew ^a   Johnson, Christopher N ^a   Matthews, Kim L ^a   Jandu, Karamjit S ^a   Meng, Wenjing ^a   Hersey, Anne ^a   Livermore, David G ^a   Douault, Clement B ^a   Witherington, Jason ^a   Bit, Rino A ^a   Rowedder, James E ^a   Brown, Jason D ^a   Clayton, Nick M ^a  

^a GLAXOSMITHKLINE   (United Kingdom)

Author keywords

Alpha 2 delta; Metasite; Neuropathic pain; P glycoprotein; Pyrazolopyridazine

Indexed keywords

ANALGESIC AGENT; GLYCOPROTEIN P; PREGABALIN; PYRAZOLOPYRIDAZINE; UNCLASSIFIED DRUG;

ANALGESIC ACTIVITY; ANIMAL MODEL; ARTICLE; COMPUTER PROGRAM; IN VITRO STUDY; IN VIVO STUDY; NEUROPATHIC PAIN; NONHUMAN; RAT;

ANALGESICS; ANIMALS; CALCIUM CHANNEL BLOCKERS; CALCIUM CHANNELS; LIGANDS; NEURALGIA; P-GLYCOPROTEIN; PYRAZOLES; PYRIDAZINES; PYRIDINES; RATS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 77955423512     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.05.026     Document Type: Article

References (29)

1. R. Felix Receptors Channels 6 1999 351
2. K. Fink, D.J. Dooley, W.P. Meder, N. Suman-Chauhan, S. Duffy, H. Clusmann, and M. Gothert Neuropharmacology 42 2002 229
3. D. McClelland, R.M. Evans, L. Barkworth, D.J. Martin, and R.H. Scott BMC Pharmacol. 4 2004 14
4. D.J. Dooley, C.A. Mieske, and S.A. Borosky Neurosci. Lett. 280 2000 107
5. Y.P. Maneuf, J. Hughes, and A.T. McKnight Pain 93 2001 191
6. D.J. Dooley, C.M. Donovan, and T.A. Pugsley J. Pharmacol. Exp. Ther. 295 2000 1086
7. C.S. Bauer, M. Nieto-Rostro, W. Rahman, A. Tran-Van-Minh, L. Ferron, L. Douglas, I. Kadurin, Y. Sri Ranjan, L. Fernandez-Alacid, N.S. Millar, A.H. Dickenson, R. Lujan, and A.C. Dolphin J. Neurosci. 29 2009 4076
8. C.-Y. Li, Y.-H. Song, E.S. Higuera, and Z.D. Luo J. Neurosci. 24 2004 8494
9. M.J. Field, Z. Li, and J.B. Schwarz J. Med. Chem. 50 2007 2569
10. J.K. Baillie, and I. Power Curr. Opin. Invest. Drugs 7 2006 33
11. G.J. Sills Curr. Opin. Pharmacol. 6 2006 108
12. J.-K. Cheng, and L.-C. Chiou J. Pharmacol. Sci. 100 2006 471
13. D.J. Dooley, C.P. Taylor, S. Donevan, and D. Feltner Trends Pharmacol. Sci. 28 2007 75
14. C.P. Taylor, T. Angelotti, and E. Frauman Epilepsy Res. 73 2009 137
15. B.A. Stearns, N. Anker, J.M. Arruda, B.T. Campbell, C. Chen, M. Cramer, T. Hu, X. Jiang, K. Park, K.K. Ren, M. Sablad, A. Santini, H. Schaffhauser, M.O. Urban, and B. Munoz Bioorg. Med. Chem. Lett. 14 2004 1295
16. T. Hu, B.A. Stearns, B.T. Campbell, J.M. Arruda, C. Chen, J. Aiyar, R.E. Bezverkov, A. Santini, H. Schaffhauser, W. Liu, S. Venkatraman, and B. Munoz Bioorg. Med. Chem. Lett. 14 2004 2031
17. C. Chen, B. Stearns, T. Hu, N. Anker, A. Santini, J.M. Arruda, B.T. Campbell, P. Datta, J. Aiyar, and B. Munoz Bioorg. Med. Chem. Lett. 16 2006 746
18. Anker, N. B.; Arruda, J. M.; Campbell, B. T.; Munoz, B.; Prasit, P.; Stearns, B. A. PCT Int. Appl. WO2004006836 A2 20040122, 2004.
19. M.J. Iadarola, J. Douglass, O. Civelli, and J.R. Naranjo Brain Res. 455 1988 205
20. C.H. Hay, M.A. Trevethick, A. Wheeldon, J.S. Browers, and J.S. De Belleroche Neuroscience 78 1997 843
21. S.G. Summerfield, A.J. Stevens, L. Cutler, M.d.C. Osuna, B. Hammond, S.-P. Tang, A. Hersey, D.J. Spalding, and P. Jeffrey J. Pharmacol. Exp. Ther. 316 2006 1282
22. Q. Wang, J.D. Rager, K. Weinstein, P.S. Kardos, G.L. Dobson, J. Li, and I.J. Hidalgo Int. J. Pharm. 288 2005 349
23. G. Cruciani, E. Carosati, B. De Boeck, K. Ethirajulu, C. Mackie, T. Howe, and R. Vianello J. Med. Chem. 48 2005 6970
24. F.R. Japp, and F. Klingemann Ann 247 1888 190
25. H.V. Patel, P.S. Fernandez, and K.A. Vyas Indian J. Chem., Sect B 29 1990 966
26. R.W. Saalfrank, and T. Lutz Angew. Chem. 102 1990 1064
27. An in vivo metabolism study of compound 4 largely confirmed the Metasite® predictions. The major metabolites found in urine were the result of O-dealkylation, oxidation on the ethyl chain and oxidation of the pyrrolidine ring and those found in bile were predominantly associated with glucuronidation of the desethyl metabolite and again oxidation of the pyrrolidine ring.
28. Compound 37: 30 mg/kg: [uBl] = 0.84 μM, [uBr] = 0.20 μM; 37 10 mg/kg: [uBl] = 0.46 μM. Compound 38: 30 mg/kg: [uBl] = 0.91 μM, [uBr] = 0.23 μM; 38 10 mg/kg: [uBl] = 0.48 μM.
29. Preliminary in vivo selectivity data was provided by the rotarod model of sedation which showed compound 14 had no effect up to a dose of 300 mg/kg. This correlates to at least a threefold window between pain relief and sedation once the non-linear relationship between exposures and dose at the higher concentrations of 30 and 300 mg/kg is taken into account. Compound 14 had an in vitro selectivity for alpha-2-delta-1 over alpha-2-delta-2 of approximately 10-fold.