Design, synthesis and biological activity of pyrazolo[1,5-a]pyrimidin-7(4H) -ones as novel Kv7/KCNQ potassium channel activators

European Journal of Medicinal Chemistry

Volumn 46, Issue 3, 2011, Pages 934-943

  Qi, Jinlong ^a   Zhang, Fan ^a   Mi, Yi ^a   Fu, Yan ^a   Xu, Wen ^b   Zhang, Diqun ^a   Wu, Yibing ^a   Du, Xiaona ^a   Jia, Qingzhong ^a   Wang, Kewei ^b   Zhang, Hailin ^a  

^a HEBEI MEDICAL UNIVERSITY   (China)

^b PEKING UNIVERSITY HEALTH SCIENCE CENTER   (China)

Author keywords

Atomic absorption Rb+ efflux assay; KCNQ2 3 channel activator; Kv7 KCNQ M channel; Pyrazolo 1,5 a pyrimidin 7(4H) ones; Whole cell patch clamp recording

Indexed keywords

5 (2,6 DICHLORO 5 FLUOROPYRIDIN 3 YL) 3 PHENYL 2 (TRIFLUOROMETHYL) PYRAZOLO[1,5 A]PYRIMIDIN 7(4H) ONE; POTASSIUM CHANNEL STIMULATING AGENT; RUBIDIUM; UNCLASSIFIED DRUG;

ARTICLE; ATOMIC ABSORPTION; CONTROLLED STUDY; DRUG ACTIVITY; DRUG DESIGN; DRUG SYNTHESIS; HIGH THROUGHPUT SCREENING; HUMAN; HUMAN CELL; HUMAN TISSUE; PATCH CLAMP; STRUCTURE ACTIVITY RELATION;

ANIMALS; ARRHYTHMIAS, CARDIAC; CHO CELLS; CRICETINAE; CRICETULUS; DRUG DESIGN; EPILEPSY; HUMANS; KCNQ POTASSIUM CHANNELS; PATCH-CLAMP TECHNIQUES; PYRAZOLES; PYRIMIDINES; RUBIDIUM; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 79951610176     PISSN: 02235234     EISSN: 17683254     Source Type: Journal    
DOI: 10.1016/j.ejmech.2011.01.010     Document Type: Article

References (43)

1. E.C. Cooper, and L.Y. Jan M-channels: neurological diseases, neuromodulation, and drug development Archives of Neurology 60 2003 496 500 (Pubitemid 36427962)
2. T.J. Jentsch Neuronal KCNQ potassium channels: physiology and role in disease Nature Reviews Neuroscience 1 2000 21 30
3. H.S. Wang, Z. Pan, W. Shi, B.S. Brown, R.S. Wymore, I.S. Cohen, J.E. Dixon, and D. McKinnon KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel Science 282 1998 1890 1893 (Pubitemid 28555268)
4. C. Charlier, N.A. Singh, S.G. Ryan, T.B. Lewis, B.E. Reus, R.J. Leach, and M. Leppert A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family (see comments) Nature Genetics 18 1998 53 55 (Pubitemid 28027879)
5. C. Biervert, B.C. Schroeder, C. Kubisch, S.F. Berkovic, P. Propping, T.J. Jentsch, and O.K. Steinlein A potassium channel mutation in neonatal human epilepsy Science 279 1998 403 406 (Pubitemid 28063379)
6. E.C. Cooper, K.D. Aldape, A. Abosch, N.M. Barbaro, M.S. Berger, W.S. Peacock, Y.N. Jan, and L.Y. Jan Colocalization and coassembly of two human brain M-type potassium channel subunits that are mutated in epilepsy Proceedings of the National Academy of Sciences 97 2000 4914 4919 (Pubitemid 30238657)
7. E.C. Cooper, E. Harrington, Y.N. Jan, and L.Y. Jan M channel KCNQ2 subunits are localized to key sites for control of neuronal network oscillations and synchronization in mouse brain Journal of Neuroscience 21 2001 9529 9540 (Pubitemid 34184041)
8. T. Ljungstrom, M. Grunnet, B.S. Jensen, and S.P. Olesen Functional coupling between heterologously expressed dopamine D(2) receptors and KCNQ channels Pflügers Archiv: European Journal of Physiology 446 2003 684 694 (Pubitemid 37215004)
9. F. Jow, and K. Wang Cloning and functional expression of rKCNQ2 K(+) channel from rat brain Brain Research Molecular Brain Research 80 2000 269 278
10. G.M. Passmore, A.A. Selyanko, M. Mistry, M. Al-Qatari, S.J. Marsh, E.A. Matthews, A.H. Dickenson, T.A. Brown, S.A. Burbidge, and M. Main KCNQ/M currents in sensory neurons: significance for pain therapy Journal of Neuroscience 23 2003 7227 7236 (Pubitemid 36975887)
11. J. Robbins KCNQ potassium channels: physiology, pathophysiology, and pharmacology Pharmacology & Therapeutics 90 2001 1 19 (Pubitemid 32622837)
12. A. Fontan-Lozano, I. Suarez-Pereira, J.M. Delgado-Garcia, and A.M. Carrion The M-current inhibitor XE991 decreases the stimulation threshold for long-term synaptic plasticity in healthy mice and in models of cognitive disease Hippocampus 2009
13. D. Kapfhamer, K.H. Berger, F.W. Hopf, T. Seif, V. Kharazia, A. Bonci, U. Heberlein, Protein phosphatase 2a and glycogen synthase kinase 3 signaling modulate prepulse inhibition of the acoustic startle response by altering cortical M-type potassium channel activity, Journal of Neuroscience 30 8830-8840.
14. A.D. Wickenden, R. Roeloffs, G. McNaughton-Smith, and G.C. Rigdon KCNQ potassium channels: drug targets for the treatment of epilepsy and pain Expert Opinion on Therapeutic Patents 14 2004 457 469 (Pubitemid 38489491)
15. D.A. Brown, and G.M. Passmore Neural KCNQ (Kv7) channels British Journal of Pharmacology 156 2009 1185 1195
16. C.g. Identifier:, NCT00232596 and NCT00235755 2008/2009 http://clinicaltrials.gov
17. A.N. Nielsen, C. Mathiesen, and G. Blackburn-Munro Pharmacological characterisation of acid-induced muscle allodynia in rats European Journal of Pharmacology 487 2004 93 103 (Pubitemid 38368985)
18. G. Blackburn-Munro, and B.S. Jensen The anticonvulsant retigabine attenuates nociceptive behaviours in rat models of persistent and neuropathic pain European Journal of Pharmacology 460 2003 109 116 (Pubitemid 36139977)
19. R. Dost, A. Rostock, and C. Rundfeldt The anti-hyperalgesic activity of retigabine is mediated by KCNQ potassium channel activation Naunyn- Schmiedeberg's Archives of Pharmacology 369 2004 382 390 (Pubitemid 38553673)
20. - channels The Journal of Clinical Investigation 120 2010 1240 1252
21. C.g. Identifier:, NCT00612105 2009 http://clinicaltrials.gov
22. R.L. Schroder, T. Jespersen, P. Christophersen, D. Strobaek, B.S. Jensen, and S.P. Olesen KCNQ4 channel activation by BMS-204352 and retigabine Neuropharmacology 40 2001 888 898 (Pubitemid 32510802)
23. M.P. Korsgaard, B.P. Hartz, W.D. Brown, P.K. Ahring, D. Strobaek, and N.R. Mirza Anxiolytic effects of Maxipost (BMS-204352) and retigabine via activation of neuronal Kv7 channels Journal of Pharmacology and Experimental Therapeutics 314 2005 282 292 (Pubitemid 41058265)
24. B.H. Bentzen, N. Schmitt, K. Calloe, W. Dalby Brown, M. Grunnet, and S.P. Olesen The acrylamide (S)-1 differentially affects Kv7 (KCNQ) potassium channels Neuropharmacology 51 2006 1068 1077 (Pubitemid 44691813)
25. A. Peretz, N. Degani, R. Nachman, Y. Uziyel, G. Gibor, D. Shabat, and B. Attali Meclofenamic acid and diclofenac, novel templates of KCNQ2/Q3 potassium channel openers, depress cortical neuron activity and exhibit anticonvulsant properties Molecular Pharmacology 67 2005 1053 1066 (Pubitemid 40410406)
26. A. Peretz, N. Degani-Katzav, M. Talmon, E. Danieli, A. Gopin, E. Malka, R. Nachman, A. Raz, D. Shabat, and B. Attali A tale of switched functions: from cyclooxygenase inhibition to M-channel modulation in new diphenylamine derivatives PLoS One 2 2007
27. A.D. Wickenden, J.L. Krajewski, B. London, P.K. Wagoner, W.A. Wilson, S. Clark, R. Roeloffs, G. McNaughton-Smith, and G.C. Rigdon N-(6-chloro-pyridin-3- yl)-3, 4-difluoro-benzamide (ICA-27243): a novel, selective KCNQ2/Q3 potassium channel activator Molecular Pharmacology 73 2008 977 986 (Pubitemid 351397902)
28. R. Roeloffs, A.D. Wickenden, C. Crean, S. Werness, G. McNaughton-Smith, J. Stables, J.O. McNamara, N. Ghodadra, and G.C. Rigdon In vivo profile of ICA-27243 [N-(6-chloro-pyridin-3-yl)-3, 4-difluoro-benzamide], a potent and selective KCNQ2/Q3 (Kv7. 2/Kv7. 3) activator in rodent anticonvulsant models Journal of Pharmacology and Experimental Therapeutics 326 2008 818 828
29. Q. Xiong, H. Sun, and M. Li Zinc pyrithione-mediated activation of voltage-gated KCNQ potassium channels rescues epileptogenic mutants Nature Chemical Biology 3 2007 287 296 (Pubitemid 46625833)
30. Q. Xiong, H. Sun, Y. Zhang, F. Nan, and M. Li Combinatorial augmentation of voltage-gated KCNQ potassium channels by chemical openers Proceedings of the National Academy of Sciences 105 2008 3128 3133 (Pubitemid 351723679)
31. L. Yu, W. Li, and Y. Li Synthesis of ethyl 1-alkyl-3-substituted-4- aminopyrazole-5-carboxylate and ethyl 1-alkyl-3-substituted-5-aminopyrazole-4- carboxylate Periodical of Ocean University of China 36 2006 54 58
32. Z. Li, Y. Liu, X. Yuan, and P. Gong Synthesis and antitumor activities of 5,7-disubstituted pyrazolo[1,5-a]pyrimidines Chinese Journal Of Medicinal Chemistry 17 2007 18 22
33. K. Paruch, M.P. Dwyer, C. Alvarez, C. Brown, T.Y. Chan, R.J. Doll, K. Keertikar, C. Knutson, B. McKittrick, and J. Rivera Pyrazolo[1,5-a]pyrimidines as orally available inhibitors of cyclin-dependent kinase 2 Bioorganic & Medicinal Chemistry Letters 17 2007 6220 6223 (Pubitemid 47552823)
34. C. Chen, K.M. Wilcoxen, C.Q. Huang, J.R. McCarthy, T. Chen, and D.E. Grigoriadis Optimization of 3-phenylpyrazolo[1,5-a]pyrimidines as potent corticotropin-releasing factor-1 antagonists with adequate lipophilicity and water solubility Bioorganic & Medicinal Chemistry Letters 14 2004 3669 3673 (Pubitemid 38760060)
35. Mitsui IC. Mitsui chemical inc (JP). Patent (china) CN1154639C.
36. Y.C. Wu, Y.J. Chen, H.J. Li, X.M. Zou, F.Z. Hu, and H.Z. Yang Synthesis of trifluoromethyl-promoted functional pyrazolo[1,5-a]pyrimidine and pyrazolo[5,1-d][1,2,3,5]tetrazine-4(3H)-ones Journal of Fluorine Chemistry 127 2006 409 416
37. K.W. Wang, B. McIlvain, E. Tseng, D. Kowal, F. Jow, R. Shen, H. Zhang, Q.J. Shan, L. He, and D. Chen Validation of an atomic absorption rubidium ion efflux assay for KCNQ/M-channels using the Ion Channel Reader 8000 Assay and Drug Development Technologies 2 2004 525 534 (Pubitemid 39619095)
38. + Channel Complexes PLoS One 4 2009 e4236
39. E. Schulze-Bahr, W. Haverkamp, H. Wedekind, C. Rubie, M. Hordt, M. Borggrefe, G. Assmann, G. Breithardt, and H. Funke Autosomal recessive long-QT syndrome (Jervell Lange-Nielsen syndrome) is genetically heterogeneous Human Genetics 100 1997 573 576 (Pubitemid 28072357)
40. S. Chen, L. Zhang, R.M. Bryant, G.M. Vincent, M. Flippin, J.C. Lee, E. Brown, F. Zimmerman, R. Rozich, P. Szafranski, C. Oberti, R. Sterba, D. Marangi, P.J. Tchou, M.K. Chung, and Q. Wang KCNQ1 mutations in patients with a family history of lethal cardiac arrhythmias and sudden death Clinical Genetics 63 2003 273 282 (Pubitemid 36957794)
41. Q. Wang, M.E. Curran, I. Splawski, T.C. Burn, J.M. Millholland, T.J. VanRaay, J. Shen, K.W. Timothy, G.M. Vincent, T. de Jager, P.J. Schwartz, J.A. Toubin, A.J. Moss, D.L. Atkinson, G.M. Landes, T.D. Connors, and M.T. Keating Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias Nature Genetics 12 1996 17 23 (Pubitemid 26011314)
42. K. Wang, B. McIlvain, E. Tseng, D. Kowal, F. Jow, R. Shen, H. Zhang, Q.J. Shan, L. He, D. Chen, Q. Lu, and J. Dunlop Validation of an atomic absorption rubidium ion efflux assay for KCNQ/M-channels using the ion Channel Reader 8000 Assay and Drug Development Technologies 2 2004 525 534 (Pubitemid 39619095)
43. + efflux through functional activation of cardiac KCNQ1/minK channels by the benzodiazepine R-L3 (L-364,373) Assay and Drug Development Technologies 4 2006 443 450 (Pubitemid 44781634)