Login Register Cart 0
Review Article

钾通道调节剂的药物化学近期进展的最新进展（2011-2017）

卷 26, 期 12, 2019

页: [2062 - 2084] 页: 23

弟呕挨: 10.2174/0929867325666180430152023

价格: $65

摘要

背景：钾（K +）通道参与许多生理过程，心脏功能，细胞增殖，神经元信号，肌肉收缩性，免疫功能，激素分泌，渗透压，基因表达的变化，并参与关键的生物学功能，并在各种疾病。钾通道代表一大类四聚体膜蛋白。钾通道激活降低了兴奋性，而通道抑制增加了兴奋性。 目的：小分子K +通道激活剂和抑制剂与电压门控，内向整流和双孔串联钾通道相互作用。由于它们参与生物功能和各种疾病，作为钾通道调节剂的小分子受到了极大的科学关注。 方法：在本综述中，我们编制了与不同化学类别的钾通道开放剂和阻断剂相关的文献，专利和专利申请（2011至2017），作为治疗各种疾病的治疗剂。在过去几年中，许多不同化学类别的选择性小分子已经出现作为钾通道调节剂。 结论：本综述讨论了目前对钾通道调节剂领域药物化学研究的理解，以更新该领域的关键进展。

关键词: 钾通道调节剂，钾通道开放剂，钾通道阻滞剂，ATP敏感性钾通道，电压门控钾通道，内向整流钾通道。

« Previous Next »
[1]
Hille, B. Ionic Channels of Excitable Membranes.In: Sinauer Associates Inc, 2nd ed; : Sunderland, MA,. , 1992.
[2]
Molokanova, E.; Savchenko, A. Bright future of optical assays for ion channel drug discovery. Drug Discov. Today, 2008, 13(1-2), 14-22.
[http://dx.doi.org/10.1016/j.drudis.2007.11.009] [PMID: 18190859]
[3]
Giorgetti, A.; Carloni, P. Molecular modeling of ion channels: structural predictions. Curr. Opin. Chem. Biol., 2003, 7(1), 150-156.
[http://dx.doi.org/10.1016/S1367-5931(02)00012-1] [PMID: 12547440]
[4]
Sandhiya, S.; Dkhar, S.A. Potassium channels in health, disease & development of channel modulators. Indian J. Med. Res., 2009, 129(3), 223-232.
[PMID: 19491413]
[5]
Clare, J.J. Targeting ion channels for drug discovery. Discov. Med., 2010, 9(46), 253-260.
[PMID: 20350493]
[6]
Minor, D.L. Handbook of Cell Signaling; Bradshaw, R.A; Dennis, E.A., Ed.; Elsevier Science B. V: Amsterdam, 2009, pp. 201-207.
[7]
MacKinnon, R. Potassium channels. FEBS Lett., 2003, 555(1), 62-65.
[http://dx.doi.org/10.1016/S0014-5793(03)01104-9] [PMID: 14630320]
[8]
Sansom, M.S.; Shrivastava, I.H.; Bright, J.N.; Tate, J.; Capener, C.E.; Biggin, P.C. Potassium channels: structures, models, simulations. Biochim. Biophys. Acta, 2002, 1565(2), 294-307.
[http://dx.doi.org/10.1016/S0005-2736(02)00576-X] [PMID: 12409202]
[9]
Miller, C. An overview of the potassium channel family. Genome Biol., 2000, 1(4), S0004.
[http://dx.doi.org/10.1186/gb-2000-1-4-reviews0004] [PMID: 11178249]
[10]
Ford, J.W.; Stevens, E.B.; Treherne, J.M.; Packer, J.; Bushfield, M. Potassium channels: gene family, therapeutic relevance, high-throughput screening technologies and drug discovery. Prog. Drug Res., 2002, 58, 133-168.
[http://dx.doi.org/10.1007/978-3-0348-8183-8_4] [PMID: 12079199]
[11]
Mannhold, R. KATP channel openers: structure-activity relationships and therapeutic potential. Med. Res. Rev., 2004, 24(2), 213-266.
[http://dx.doi.org/10.1002/med.10060] [PMID: 14705169]
[12]
Minor, D.L. Jr Potassium channels: life in the post-structural world. Curr. Opin. Struct. Biol., 2001, 11(4), 408-414.
[http://dx.doi.org/10.1016/S0959-440X(00)00225-6] [PMID: 11495731]
[13]
Wickenden, A.D. Potassium channels as anti-epileptic drug targets. Neuropharmacology, 2002, 43(7), 1055-1060.
[http://dx.doi.org/10.1016/S0028-3908(02)00237-X] [PMID: 12504910]
[14]
Wang, Y.; Yang, P.L.; Tang, J.F.; Lin, J.F.; Cai, X.H.; Wang, X.T.; Zheng, G.Q. Potassium channels: possible new therapeutic targets in Parkinson’s disease. Med. Hypotheses, 2008, 71(4), 546-550.
[http://dx.doi.org/10.1016/j.mehy.2008.05.021] [PMID: 18650029]
[15]
McKeon, A.; Marnane, M.; O’connell, M.; Stack, J.P.; Kelly, P.J.; Lynch, T. Potassium channel antibody associated encephalopathy presenting with a frontotemporal dementia like syndrome. Arch. Neurol., 2007, 64(10), 1528-1530.
[http://dx.doi.org/10.1001/archneur.64.10.1528] [PMID: 17923638]
[16]
Mitra, R.; Ferguson, D.; Sapolsky, R.M. SK2 potassium channel overexpression in basolateral amygdala reduces anxiety, stress-induced corticosterone secretion and dendritic arborization. Mol. Psychiatry, 2009. 14(9), 847-855, 827.
[http://dx.doi.org/10.1038/mp.2009.9] [PMID: 19204724]
[17]
Takeda, M.; Tsuboi, Y.; Kitagawa, J.; Nakagawa, K.; Iwata, K.; Matsumoto, S. Potassium channels as a potential therapeutic target for trigeminal neuropathic and inflammatory pain. Mol. Pain, 2011, 7(5), 5.
[http://dx.doi.org/10.1186/1744-8069-7-5] [PMID: 21219657]
[18]
Jenkins, D.P.; Maezawa, I.; Wulff, H.; Jin, L.W. Microglial Kv1.3 channels as a potential target for Alzheimer’s disease. Int. J. Alzheimers Dis., 2012, 2012, 1-8.
[19]
Heurteaux, C.; Lucas, G.; Guy, N.; El Yacoubi, M.; Thümmler, S.; Peng, X.D.; Noble, F.; Blondeau, N.; Widmann, C.; Borsotto, M.; Gobbi, G.; Vaugeois, J.M.; Debonnel, G.; Lazdunski, M. Deletion of the background potassium channel TREK-1 results in a depression-resistant phenotype. Nat. Neurosci., 2006, 9(9), 1134-1141.
[http://dx.doi.org/10.1038/nn1749] [PMID: 16906152]
[20]
Zhang, L.; Li, X.; Zhou, R.; Xing, G. Possible role of potassium channel, big K in etiology of schizophrenia. Med. Hypotheses, 2006, 67(1), 41-43.
[http://dx.doi.org/10.1016/j.mehy.2005.09.055] [PMID: 16446048]
[21]
Carlsson, L.; Abrahamsson, C.; Drews, L.; Duker, G. Antiarrhythmic effects of potassium channel openers in rhythm abnormalities related to delayed repolarization. Circulation, 1992, 85(4), 1491-1500.
[http://dx.doi.org/10.1161/01.CIR.85.4.1491] [PMID: 1555289]
[22]
Sobey, C.G. Potassium channel function in vascular disease. Arterioscler. Thromb. Vasc. Biol., 2001, 21(1), 28-38.
[http://dx.doi.org/10.1161/01.ATV.21.1.28] [PMID: 11145930]
[23]
Huang, X.; Jan, L.Y. Targeting potassium channels in cancer. J. Cell Biol., 2014, 206(2), 151-162.
[http://dx.doi.org/10.1083/jcb.201404136] [PMID: 25049269]
[24]
Wickenden, A.K. (+) channels as therapeutic drug targets. Pharmacol. Ther., 2002, 94(1-2), 157-182.
[http://dx.doi.org/10.1016/S0163-7258(02)00201-2] [PMID: 12191600]
[25]
Sanguinetti, M.C.; Jiang, C.; Curran, M.E.; Keating, M.T. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell, 1995, 81(2), 299-307.
[http://dx.doi.org/10.1016/0092-8674(95)90340-2] [PMID: 7736582]
[26]
Coghlan, M.J.; Carroll, W.A.; Gopalakrishnan, M. Recent developments in the biology and medicinal chemistry of potassium channel modulators: update from a decade of progress. J. Med. Chem., 2001, 44(11), 1627-1653.
[http://dx.doi.org/10.1021/jm000484+] [PMID: 11356099]
[27]
Zhou, Y.; Morais-Cabral, J.H.; Kaufman, A.; MacKinnon, R. Chemistry of ion coordination and hydration revealed by a K+ channel-Fab complex at 2.0 A resolution. Nature, 2001, 414(6859), 43-48.
[http://dx.doi.org/10.1038/35102009] [PMID: 11689936]
[28]
Morais-Cabral, J.H.; Zhou, Y.; MacKinnon, R. Energetic optimization of ion conduction rate by the K+ selectivity filter. Nature, 2001, 414(6859), 37-42.
[http://dx.doi.org/10.1038/35102000] [PMID: 11689935]
[29]
Bernèche, S.; Roux, B. Energetics of ion conduction through the K+ channel. Nature, 2001, 414(6859), 73-77.
[http://dx.doi.org/10.1038/35102067] [PMID: 11689945]
[30]
Tian, C.; Zhu, R.; Zhu, L.; Qiu, T.; Cao, Z.; Kang, T. Potassium channels: structures, diseases, and modulators. Chem. Biol. Drug Des., 2014, 83(1), 1-26.
[http://dx.doi.org/10.1111/cbdd.12237] [PMID: 24119115]
[31]
Lawson, K. Potassium channel activation: a potential therapeutic approach? Pharmacol. Ther., 1996, 70(1), 39-63.
[http://dx.doi.org/10.1016/0163-7258(96)00003-4] [PMID: 8804110]
[32]
Ptácek, L.J.; Fu, Y.H. Channels and disease: past, present, and future. Arch. Neurol., 2004, 61(11), 1665-1668.
[http://dx.doi.org/10.1001/archneur.61.11.1665] [PMID: 15534176]
[33]
Jenkinson, D.H. Potassium channels--multiplicity and challenges. Br. J. Pharmacol., 2006, 147(S1)(Suppl. 1), S63-S71.
[http://dx.doi.org/10.1038/sj.bjp.0706447] [PMID: 16402122]
[34]
Wei, A.; Jegla, T.; Salkoff, L. Eight potassium channel families revealed by the C. elegans genome project. Neuropharmacology, 1996, 35(7), 805-829.
[http://dx.doi.org/10.1016/0028-3908(96)00126-8] [PMID: 8938713]
[35]
Ye, D.; Wang, J.; Yu, K.; Zhou, Y.; Jiang, H.; Chen, K.; Liu, H. Current strategies for the discovery of K+ channel modulators. Curr. Top. Med. Chem., 2009, 9(4), 348-361.
[http://dx.doi.org/10.2174/156802609788317865] [PMID: 19442206]
[36]
Shieh, C.C.; Coghlan, M.; Sullivan, J.P.; Gopalakrishnan, M. Potassium channels: molecular defects, diseases, and therapeutic opportunities. Pharmacol. Rev., 2000, 52(4), 557-594.
[PMID: 11121510]
[37]
Lawson, K.; McKay, N.G. Modulation of potassium channels as a therapeutic approach. Curr. Pharm. Des., 2006, 12(4), 459-470.
[http://dx.doi.org/10.2174/138161206775474477] [PMID: 16472139]
[38]
Gutman, G.A.; Chandy, K.G.; Grissmer, S.; Lazdunski, M.; McKinnon, D.; Pardo, L.A.; Robertson, G.A.; Rudy, B.; Sanguinetti, M.C.; Stühmer, W.; Wang, X. International Union of Pharmacology. LIII. Nomenclature and molecular relationships of voltage-gated potassium channels. Pharmacol. Rev., 2005, 57(4), 473-508.
[http://dx.doi.org/10.1124/pr.57.4.10] [PMID: 16382104]
[39]
Kubo, Y.; Adelman, J.P.; Clapham, D.E.; Jan, L.Y.; Karschin, A.; Kurachi, Y.; Lazdunski, M.; Nichols, C.G.; Seino, S.; Vandenberg, C.A. International Union of Pharmacology. LIV. Nomenclature and molecular relationships of inwardly rectifying potassium channels. Pharmacol. Rev., 2005, 57(4), 509-526.
[http://dx.doi.org/10.1124/pr.57.4.11] [PMID: 16382105]
[40]
Goldstein, S.A.; Bayliss, D.A.; Kim, D.; Lesage, F.; Plant, L.D.; Rajan, S. International Union of Pharmacology. LV. Nomenclature and molecular relationships of two-P potassium channels. Pharmacol. Rev., 2005, 57(4), 527-540.
[41]
Gutman, G.A.; Chandy, K.G.; Adelman, J.P.; Aiyar, J.; Bayliss, D.A.; Clapham, D.E.; Covarriubias, M.; Desir, G.V.; Furuichi, K.; Ganetzky, B.; Garcia, M.L.; Grissmer, S.; Jan, L.Y.; Karschin, A.; Kim, D.; Kuperschmidt, S.; Kurachi, Y.; Lazdunski, M.; Lesage, F.; Lester, H.A.; McKinnon, D.; Nichols, C.G.; O’Kelly, I.; Robbins, J.; Robertson, G.A.; Rudy, B.; Sanguinetti, M.; Seino, S.; Stuehmer, W.; Tamkun, M.M.; Vandenberg, C.A.; Wei, A.; Wulff, H.; Wymore, R.S. International Union of Pharmacology. XLI. Compendium of voltage-gated ion channels: potassium channels. Pharmacol. Rev., 2003, 55(4), 583-586.
[http://dx.doi.org/10.1124/pr.55.4.9] [PMID: 14657415]
[42]
Wei, A.D.; Gutman, G.A.; Aldrich, R.; Chandy, K.G.; Grissmer, S.; Wulff, H. International Union of Pharmacology. LII. Nomenclature and molecular relationships of calcium-activated potassium channels. Pharmacol. Rev., 2005, 57(4), 463-472.
[http://dx.doi.org/10.1124/pr.57.4.9] [PMID: 16382103]
[43]
Yellen, G. The voltage-gated potassium channels and their relatives. Nature, 2002, 419(6902), 35-42.
[http://dx.doi.org/10.1038/nature00978] [PMID: 12214225]
[44]
Camerino, D.C.; Tricarico, D.; Desaphy, J.F. Ion channel pharmacology. Neurotherapeutics, 2007, 4(2), 184-198.
[http://dx.doi.org/10.1016/j.nurt.2007.01.013] [PMID: 17395128]
[45]
del Camino, D.; Yellen, G. Tight steric closure at the intracellular activation gate of a voltage-gated K(+) channel. Neuron, 2001, 32(4), 649-656.
[http://dx.doi.org/10.1016/S0896-6273(01)00487-1] [PMID: 11719205]
[46]
Abraham, M.R.; Jahangir, A.; Alekseev, A.E.; Terzic, A. Channelopathies of inwardly rectifying potassium channels. FASEB J., 1999, 13(14), 1901-1910.
[http://dx.doi.org/10.1096/fasebj.13.14.1901] [PMID: 10544173]
[47]
Hibino, H.; Inanobe, A.; Furutani, K.; Murakami, S.; Findlay, I.; Kurachi, Y. Inwardly rectifying potassium channels: their structure, function, and physiological roles. Physiol. Rev., 2010, 90(1), 291-366.
[http://dx.doi.org/10.1152/physrev.00021.2009] [PMID: 20086079]
[48]
Dahal, G.R.; Rawson, J.; Gassaway, B.; Kwok, B.; Tong, Y.; Ptácek, L.J.; Bates, E. An inwardly rectifying K+ channel is required for patterning. Development, 2012, 139(19), 3653-3664.
[http://dx.doi.org/10.1242/dev.078592] [PMID: 22949619]
[49]
Lu, Z. Mechanism of rectification in inward-rectifier K+ channels. Annu. Rev. Physiol., 2004, 66, 103-129.
[http://dx.doi.org/10.1146/annurev.physiol.66.032102.150822] [PMID: 14977398]
[50]
Robbins, J. KCNQ potassium channels: physiology, pathophysiology, and pharmacology. Pharmacol. Ther., 2001, 90(1), 1-19.
[http://dx.doi.org/10.1016/S0163-7258(01)00116-4] [PMID: 11448722]
[51]
Kloukina, V.; Herzer, S.; Karlsson, N.; Perez, M.; Daraio, T.; Meister, B. G-protein-gated inwardly rectifying K+ channel 4 (GIRK4) immunoreactivity in chemically defined neurons of the hypothalamic arcuate nucleus that control body weight. J. Chem. Neuroanat., 2012, 44(1), 14-23.
[http://dx.doi.org/10.1016/j.jchemneu.2012.03.003] [PMID: 22465809]
[52]
Aguilar-Bryan, L.; Clement, J.P.I.V., IV; Gonzalez, G.; Kunjilwar, K.; Babenko, A.; Bryan, J. Toward understanding the assembly and structure of KATP channels. Physiol. Rev., 1998, 78(1), 227-245.
[http://dx.doi.org/10.1152/physrev.1998.78.1.227] [PMID: 9457174]
[53]
Lu, Z.; Klem, A.M.; Ramu, Y. Ion conduction pore is conserved among potassium channels. Nature, 2001, 413(6858), 809-813.
[http://dx.doi.org/10.1038/35101535] [PMID: 11677598]
[54]
Es-Salah-Lamoureux, Z.; Steele, D.F.; Fedida, D. Research into the therapeutic roles of two-pore-domain potassium channels. Trends Pharmacol. Sci., 2010, 31(12), 587-595.
[http://dx.doi.org/10.1016/j.tips.2010.09.001] [PMID: 20951446]
[55]
Lesage, F. Pharmacology of neuronal background potassium channels. Neuropharmacology, 2003, 44(1), 1-7.
[http://dx.doi.org/10.1016/S0028-3908(02)00339-8] [PMID: 12559116]
[56]
Bayliss, D.A.; Barrett, P.Q. Emerging roles for two-pore-domain potassium channels and their potential therapeutic impact. Trends Pharmacol. Sci., 2008, 29(11), 566-575.
[http://dx.doi.org/10.1016/j.tips.2008.07.013] [PMID: 18823665]
[57]
Enyedi, P.; Czirják, G. Molecular background of leak K+ currents: two-pore domain potassium channels. Physiol. Rev., 2010, 90(2), 559-605.
[http://dx.doi.org/10.1152/physrev.00029.2009] [PMID: 20393194]
[58]
Lesage, F.; Lazdunski, M. Molecular and functional properties of two-pore-domain potassium channels. Am. J. Physiol. Renal Physiol., 2000, 279(5), F793-F801.
[http://dx.doi.org/10.1152/ajprenal.2000.279.5.F793] [PMID: 11053038]
[59]
Franks, N.P. Molecular targets underlying general anaesthesia. Br. J. Pharmacol., 2006, 147(1)(Suppl. 1), S72-S81.
[PMID: 16402123]
[60]
Wulff, H.; Zhorov, B.S.K.K. + channel modulators for the treatment of neurological disorders and autoimmune diseases. Chem. Rev., 2008, 108(5), 1744-1773.
[http://dx.doi.org/10.1021/cr078234p] [PMID: 18476673]
[61]
Nardi, A.; Olesen, S.P. BK channel modulators: a comprehensive overview. Curr. Med. Chem., 2008, 15(11), 1126-1146.
[http://dx.doi.org/10.2174/092986708784221412] [PMID: 18473808]
[62]
Nardi, A.; Demnitz, J.; Garcia, M.L.; Polosa, R. Potassium channels as drug targets for therapeutic intervention in respiratory diseases. Expert Opin. Ther. Pat., 2008, 18, 1361-1384.
[http://dx.doi.org/10.1517/13543770802553798]
[63]
Bano, M.; Barot, K.P.; Ahmed, S.M.; Nikolova, S.; Ivanov, I.; Ghate, M.D. Benzopyran derivatives as cardio-selective ATP-sensitive potassium channel openers: a review. Mini Rev. Med. Chem., 2013, 13(12), 1744-1760.
[http://dx.doi.org/10.2174/13895575113136660084] [PMID: 24032515]
[64]
Qi, J.; Zhang, F.; Mi, Y.; Fu, Y.; Xu, W.; Zhang, D.; Wu, Y.; Du, X.; Jia, Q.; Wang, K.; Zhang, H. Design, synthesis and biological activity of pyrazolo[1,5-a]pyrimidin-7(4H)-ones as novel Kv7/KCNQ potassium channel activators. Eur. J. Med. Chem., 2011, 46(3), 934-943.
[http://dx.doi.org/10.1016/j.ejmech.2011.01.010] [PMID: 21296466]
[65]
Khelili, S.; Kihal, N.; Yekhlef, M.; de Tullio, P.; Lebrun, P.; Pirotte, B. Synthesis and pharmacological activity of N-(2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4-yl)-4H-1,2,4-benzothiadiazine-3-carboxamides 1,1-dioxides on rat uterus, rat aorta and rat pancreatic β-cells. Eur. J. Med. Chem., 2012, 54, 873-878.
[http://dx.doi.org/10.1016/j.ejmech.2012.05.011] [PMID: 22647221]
[66]
de Tullio, P.; Servais, A.C.; Fillet, M.; Gillotin, F.; Somers, F.; Chiap, P.; Lebrun, P.; Pirotte, B. Hydroxylated analogues of ATP-sensitive potassium channel openers belonging to the group of 6- and/or 7-substituted 3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides: toward an improvement in sulfonylurea receptor 1 selectivity and metabolism stability. J. Med. Chem., 2011, 54(24), 8353-8361.
[http://dx.doi.org/10.1021/jm200786z] [PMID: 22077416]
[67]
Constant-Urban, C.; Charif, M.; Goffin, E.; Van Heugen, J.C.; Elmoualij, B.; Chiap, P.; Mouithys-Mickalad, A.; Serteyn, D.; Lebrun, P.; Pirotte, B.; De Tullio, P. Triphenylphosphonium salts of 1,2,4-benzothiadiazine 1,1-dioxides related to diazoxide targeting mitochondrial ATP-sensitive potassium channels. Bioorg. Med. Chem. Lett., 2013, 23(21), 5878-5881.
[http://dx.doi.org/10.1016/j.bmcl.2013.08.091] [PMID: 24055044]
[68]
Carvalho, J.F.; Louvel, J.; Doornbos, M.L.; Klaasse, E.; Yu, Z.; Brussee, J.; IJzerman, A.P. Strategies to reduce HERG K+ channel blockade. Exploring heteroaromaticity and rigidity in novel pyridine analogues of dofetilide. J. Med. Chem., 2013, 56(7), 2828-2840.
[http://dx.doi.org/10.1021/jm301564f] [PMID: 23473309]
[69]
Amato, G.; Roeloffs, R.; Rigdon, G.C.; Antonio, B.; Mersch, T.; McNaughton-Smith, G.; Wickenden, A.D.; Fritch, P.; Suto, M.J. N-pyridyl and pyrimidine benzamides as KCNQ2/Q3 potassium channel openers for the treatment of epilepsy. ACS Med. Chem. Lett., 2011, 2(6), 481-484.
[http://dx.doi.org/10.1021/ml200053x] [PMID: 24900334]
[70]
Martelli, A.; Manfroni, G.; Sabbatini, P.; Barreca, M.L.; Testai, L.; Novelli, M.; Sabatini, S.; Massari, S.; Tabarrini, O.; Masiello, P.; Calderone, V.; Cecchetti, V. 1,4-Benzothiazine ATP-sensitive potassium channel openers: modifications at the C-2 and C-6 positions. J. Med. Chem., 2013, 56(11), 4718-4728.
[http://dx.doi.org/10.1021/jm400435a] [PMID: 23662847]
[71]
Wu, Y.J.; Conway, C.M.; Sun, L.Q.; Machet, F.; Chen, J.; Chen, P.; He, H.; Bourin, C.; Calandra, V.; Polino, J.L.; Davis, C.D.; Heman, K.; Gribkoff, V.K.; Boissard, C.G.; Knox, R.J.; Thompson, M.W.; Fitzpatrick, W.; Weaver, D.; Harden, D.G.; Natale, J.; Dworetzky, S.I.; Starrett, J.E. Jr Discovery of (S,E)-3-(2-fluorophenyl)-N-(1-(3-(pyridin-3-yloxy)phenyl)ethyl)-acrylamide as a potent and efficacious KCNQ2 (Kv7.2) opener for the treatment of neuropathic pain. Bioorg. Med. Chem. Lett., 2013, 23(22), 6188-6191.
[http://dx.doi.org/10.1016/j.bmcl.2013.08.092] [PMID: 24070783]
[72]
Pirotte, B.; de Tullio, P.; Florence, X.; Goffin, E.; Somers, F.; Boverie, S.; Lebrun, P. 1,4,2-Benzo/pyridodithiazine 1,1-dioxides structurally related to the ATP-sensitive potassium channel openers 1,2,4-Benzo/pyridothiadiazine 1,1-dioxides exert a myorelaxant activity linked to a distinct mechanism of action. J. Med. Chem., 2013, 56(8), 3247-3256.
[http://dx.doi.org/10.1021/jm301743b] [PMID: 23517501]
[73]
Pirotte, B.; de Tullio, P.; Boverie, S.; Michaux, C.; Lebrun, P. Impact of the nature of the substituent at the 3-position of 4H-1,2,4-benzothiadiazine 1,1-dioxides on their opening activity toward ATP-sensitive potassium channels. J. Med. Chem., 2011, 54(9), 3188-3199.
[http://dx.doi.org/10.1021/jm200100c] [PMID: 21428460]
[74]
Florence, X.; Dilly, S.; de Tullio, P.; Pirotte, B.; Lebrun, P. Modulation of the 6-position of benzopyran derivatives and inhibitory effects on the insulin releasing process. Bioorg. Med. Chem., 2011, 19(13), 3919-3928.
[http://dx.doi.org/10.1016/j.bmc.2011.05.040] [PMID: 21664825]
[75]
Yu, H.; Wu, M.; Townsend, S.D.; Zou, B.; Long, S.; Daniels, J.S.; McManus, O.B.; Li, M.; Lindsley, C.W.; Hopkins, C.R. Discovery, synthesis, and structure activity relationship of a series of N-aryl-bicyclo[2.2.1]heptane-2-carboxamides: characterization of ML213 as a vovel KCNQ2 and KCNQ4 potassium channel opener. ACS Chem. Neurosci., 2011, 2(10), 572-577.
[http://dx.doi.org/10.1021/cn200065b] [PMID: 22125664]
[76]
Rapposelli, S.; Breschi, M.C.; Calderone, V.; Digiacomo, M.; Martelli, A.; Testai, L.; Vanni, M.; Balsamo, A. Synthesis and biological evaluation of 5-membered spiro heterocycle-benzopyran derivatives against myocardial ischemia. Eur. J. Med. Chem., 2011, 46(3), 966-973.
[http://dx.doi.org/10.1016/j.ejmech.2011.01.003] [PMID: 21288603]
[77]
Bouider, N.; Fhayli, W.; Ghandour, Z.; Boyer, M.; Harrouche, K.; Florence, X.; Pirotte, B.; Lebrun, P.; Faury, G.; Khelili, S. Design and synthesis of new potassium channel activators derived from the ring opening of diazoxide: study of their vasodilatory effect, stimulation of elastin synthesis and inhibitory effect on insulin release. Bioorg. Med. Chem., 2015, 23(8), 1735-1746.
[http://dx.doi.org/10.1016/j.bmc.2015.02.043] [PMID: 25773016]
[78]
Harrouche, K.; Renard, J.F.; Bouider, N.; de Tullio, P.; Goffin, E.; Lebrun, P.; Faury, G.; Pirotte, B.; Khelili, S. Synthesis, characterization and biological evaluation of benzothiazoles and tetrahydrobenzothiazoles bearing urea or thiourea moieties as vasorelaxants and inhibitors of the insulin releasing process. Eur. J. Med. Chem., 2016, 115, 352-360.
[http://dx.doi.org/10.1016/j.ejmech.2016.03.028] [PMID: 27031211]
[79]
Pirotte, B.; Florence, X.; Goffin, E.; Medeiros, M.B.; de Tullio, P.; Lebrun, P. 4-Phenylureido/thioureido-substituted 2,2-dimethylchroman analogs of cromakalim bearing a bulky ‘carbamate’ moiety at the 6-position as potent inhibitors of glucose-sensitive insulin secretion. Eur. J. Med. Chem., 2016, 121, 338-351.
[http://dx.doi.org/10.1016/j.ejmech.2016.05.042] [PMID: 27267004]
[80]
Zidar, N.; Žula, A.; Tomašič, T.; Rogers, M.; Kirby, R.W.; Tytgat, J.; Peigneur, S.; Kikelj, D.; Ilaš, J.; Mašič, L.P. Clathrodin, hymenidin and oroidin, and their synthetic analogues as inhibitors of the voltage-gated potassium channels. Eur. J. Med. Chem., 2017, 139, 232-241.
[http://dx.doi.org/10.1016/j.ejmech.2017.08.015] [PMID: 28802123]
[81]
Natchimuthu, V.; Bandaru, S.; Nayarisseri, A.; Ravi, S. Design, synthesis and computational evaluation of a novel intermediate salt of N-cyclohexyl-N-(cyclohexylcarbamoyl)-4-(trifluoromethyl) benzamide as potential potassium channel blocker in epileptic paroxysmal seizures. Comput. Biol. Chem., 2016, 64, 64-73.
[http://dx.doi.org/10.1016/j.compbiolchem.2016.05.003] [PMID: 27266485]
[82]
Vernier, J.M.; Delarosa, M.; Chen, H.; Wu, J.Z.; Larson, G.L.; Cheney, L.W. Derivatives of 4-(N-azacycloalkyl) anilides as potassium channel modulators. World Patent WO2011094186A1., 2011.
[83]
Christos, T.E.; Amato, G.S.; Atkinson, R.N.; Barolli, M.G.; Wolf-Gouveia, L.A.; Suto, M.J. Heterocycles as potassium channel modulators. World Patent WO2011102964 A1., 2011.
[84]
Sørensen, U.S.; Teuber, L.; Peters, D.; Strøbæk, D.; Johansen, T.H.; Nielsen, K.S.; Christophersen, P. Novel 2-amino benzimidazole derivatives and their use as modulators of smallconductance calcium-activated potassi-um channels. Eur Patent EP2319512A1., 2011.
[85]
Vernier, J.M. Naphthyridine derivatives as potassium channel modulators. Eur Patent EP2183250B1., 2011.
[86]
Wu, J.Z.; Vernier, J.M.; Chen, H.; Song, J. Benzyloxy anilide derivatives useful as potassium channel modulators. Eur Patent EP2310369A1., 2011.
[87]
Chen, H.; Song, J.; Vernier, J.M.; Wu, J.Z. 1,4 diamino bicyclic retigabine analogues as potassium channel modulators. Eur Patent EP2086925B1., 2011.
[88]
Chen, H.; Vernier, J.M. Substituted arylamino-1,2,3,4- tetrahydro naphthalenes and-2,3-dihydro-1H-indenes as potassium channel modulators. US Patent US7960436B2., 2011.
[89]
Sorensen, U.S.; Eriksen, B.L.; Teuber, L.; Peters, D.; Strobaek, D.; Johansen, T.H.; Christophersen, P. 2-aminio-pyridine derivatives and their use as potassium channel modulators. US Patent US8039632B2., 2011.
[90]
Christos, T.E.; Amato, G.S.; Atkinson, R.N.; Barolli, M.G.; Wolf-Gouveia, L.A.; Suto, M.J. Heterocycles as potassium channel modulators. US Patent US8058274B2., 2011.
[91]
Lloyd, J.; Jeon, Y.T.; Finlay, H.; Yan, L.; Beaudoin, S.; Gross, M.F. Heterocyclo inhibitors of potassium channel function. Eur Patent EP2228065B1., 2012.
[92]
Vernier, J.M.; Ouk, S.; Alicia De, L.R.M. Derivatives of 4-(Nazacycloalkyl) anilides as potassium channel modulators. Eur Patent EP2170861B1., 2012.
[93]
Zhang, X.; Li, X.; Sui, Z. Novel benzopyran derivatives as potassium channel openers. Eur Patent EP1937669B1., 2012.
[94]
Sakurada, I.; Zhang, L. Pyridmidones for treatment of potassium channel related diseases. World Patent WO2012038850 A1., 2012.
[95]
Bunnelle, W.H.; Degoey, D.; Osuma, A.T.; Patel, J.R.; Peddi, S.; Perez-Medrano, A.; Scanio, M.J.; Shi, L.; Van, C.J.; Xu, X. Pyrazolo [1, 5 -a] pyrimidin Potassium channel modulators. World Patent WO2012067822A1., 2012.
[96]
Degoey, D.; Peddi, S.; Perez-Medrano, A. A. Potassium channel modulators. World Patent WO2012067824A1., 2012.
[97]
Brown, B.S.; Degoey, D.; Li, T.; Peddi, S.; Perez-Medrano, A. A. Condensed 2-Carbamoylpyridazinines as Potassium channel modulators. World Patent WO2012158399A1., 2012.
[98]
Vernier, J.M.; Chen, H.; Song, J. Derivatives of 5-amino-4,6- disubstituted indole and 5-amino-4,6-disubstituted indoline as potassium channel mod-ulators. US Patent US8211918B2., 2012.
[99]
Eriksen, B.L.; Hougaard, C.; Peters, D.; Christophersen, P. Substituted purinyl-pyrazole derivatives and their use as potassium channel modulators. US Patent US8268838B2, 2012.
[100]
Attali, B.; Peretz, A. Derivatives of N-phenylanthranilic acid and 2-benzimidazolone as potassium channel and/or neuron activi- ty modulators. US Patent US8278357B2., 2012.
[101]
McNaughton-Smith, G.A.; Amato, G.S.; Thomas, J.B., Jr Fused ring heterocycles as potassium channel modulators. US Patent US8329713B2., 2012.
[102]
Chen, H.; Vernier, J.M. Substituted arylamino-1,2,3,4- tetrahydro naphthalenes and -2,3-dihydro-1H-indenes as potassium channel modulators. US Patent US8338487B2., 2012.
[103]
Eriksen, B.L.; Sørensen, U.S.; Hougaard, C.; Peters, D.; Johansen, T.H.; Christophersen, P. Purinyl derivatives and their use as potassium channel modulators. Eur Patent EP2402341A2., 2012.
[104]
Dinsmore, C.J.; Bergman, J.M.; Beshore, D.C.; Trotter, B.W.; Nanda, K.K.; Isaacs, R.; Payne, L.S.; Neilson, L.A.; Wu, Z.; Bilodeau, M.T.; Manley, P.J.; Balitza, A.E. Potassium channel inhibitors. Eur Patent EP1781635B1., 2012.
[105]
Dinsmore, C.J.; Bergman, J.M. Quinoline potassium channel inhibitors. Eur Patent EP1667973B1., 2013.
[106]
Gouliaev, A.H.; Slök, F.A.; Teuber, L.; Demnitz, J. Potassium channel modulators. Eur Patent EP1911740 B1., 2013.
[107]
Mcnaughton-Smith, G.A.; Amato, G.S.; Thomas, J.B., Jr Fused ring heterocycles as potassium channel modulators. Eur Patent EP1663237B1., 2013.
[108]
Christos, T.E.; Amato, G.S.; Atkinson, R.N.; Barolli, M.G.; Wolf-Gouveia, L.A.; Suto, M.J. Heterocycles as potassium channel modulators. Eur Patent EP2178373B1., 2013.
[109]
Edwards, S.D.; Kimberley, M.R.; Suthaharan, K.; Khan, N.M.; Lawton, G. Potassium ion channel modulators and uses thereof. Eur Patent EP2231594B1., 2013.
[110]
Eriksen, B.L.; Sorensen, U.S.; Hougaard, C.; Peters, D.; Christophersen, P. Pyrazine derivatives and their use as potassium channel modulators. US Patent US8415358B2., 2013.
[111]
Christos, T.E.; Amato, G.S.; Atkinson, R.N.; Barolli, M.G.; Wolf-Gouveia, L.A.; Suto, M.J. Heterocycles as potassium channel modulators. US Patent US8431608B2., 2013.
[112]
Christos, T.E.; Amato, G.S.; Atkinson, R.N.; Barolli, M.G.; Wolf-Gouveia, L.A.; Suto, M.J. Heterocycles as potassium channel modulators. US Patent US20130143889A1., 2013.
[113]
Edwards, S.D.; Kimberley, M.R.; Suthaharan, K.; Khan, N.M.; Lawton, G. Potassium ion channel modulators and uses thereof. US Patent US8466201B2., 2013.
[114]
Wu, J.Z.; Vernier, J.M.; Chen, H.; Song, J. Benzyloxy anilide derivatives useful as potassium channel modulators. US Patent US8492588B2., 2013.
[115]
Vernier, J.M.; De la Rosa, M. Naphthyridine derivatives as potassium channel modulators. US Patent US8563566B2., 2013.
[116]
Eriksen, B.L.; Hougaard, C.; Peters, D.; Christophersen, P. Pyrazolyl-pyrimidine derivatives and their use as potassium channel modulators. US Patent US8618099B2., 2013.
[117]
Perez-Medrano, A.; Peddi, S.; DeGoey, D. Potassium channel modulators. US Patent US8609674B2., 2013.
[118]
Xu, X.; Camp, J.V.; Scanio, M.J.; Bunnelle, W.H.; Shi, L.; Osuma, A.T.; DeGoey, D.; Perez-Medrano, A.; Peddi, S.; Patel, J.R. Potassium channel modulators. US Patent US8609669B2., 2013.
[119]
Sørensen, U.S.; Grunnet, M.; Bentzen, B.H.; Christophersen, P.; Diness, J.G.; Skibsbye, L.; Strøbæk, D. Benzimidazolylacetamide derivatives useful as potassium channel modulators. World Patent WO2013104577A1., 2013.
[120]
Alvaro, G.; Marasco, A. Isobenzofuran-5-yl-oxy-(hetero) arylimidazolidine -2,4-dione derivatives modulators of kv3 potassium channels for the treatment of CNS disorders. World Patent WO2013182850A1., 2013.
[121]
John, D.E.; Hartzoulakis, B.; Edwards, S.D. Thieno [2,3-c] pyrazoles for use as potassium channel inhib-itors. World Patent WO2013072693A1., 2013.
[122]
Madge, D.; Chan, F.; John, D.E.; Edwards, S.D.; Blunt, R.; Hartzoulakis, B.; Brown, L. Thieno- and furo - pyrimidines and pyridines, useful as po-tassium channel inhibitors. World Patent WO2013072694A1., 2013.
[123]
Pasternak, A.; Blizzard, T.; Chobanian, H.; Reynalda De, J.; Ding, F.X.; Dong, S.; Gude, C.; Kim, D.; Tang, H.; Walsh, S.; Pio, B.; Jiang, J. Inhibitors of the renal outer medullary potassium channel. World Patent WO2013028474A1., 2013.
[124]
Cowen, N.M.; Pasternark, R.C. Salts of potassium ATP channel openers and uses thereof. World Patent WO2013130411A1., 2013.
[125]
Finlay, H.; Adisechan, A.K.; Gunaga, P.; Lloyd, J.; Srinivasu, P. Pyrrolotriazines as potassium ion channel inhibitors. World Patent WO2014143606A1., 2014.
[126]
Finlay, H.; Adisechan, A.K.; Gunaga, P.; Lloyd, J.; Srinivasu, P. Pyrrolotriazines as potassium ion channel inhibitors. World Patent WO2014143607A1., 2014.
[127]
Finlay, H.; Adisechan, A.K.; Dhondi, N.K.; Gunaga, P.; Lloyd, J.; Srinivasu, P. Isoquinolines as potassium ion channel inhibitors. World Patent WO2014143609A1., 2014.
[128]
Finlay, H.; Adisechan, A.K.; Gunaga, P.; Lloyd, J.; Srinivasu, P. Phthalazines as potassium ion channel inhibitors. World Patent WO2014143608A1., 2014.
[129]
Finlay, H.; Adisechan, A.K.; Gunaga, P.; Dhondi, N.K.; Kavitha, G.; Lloyd, J.; Srinivasu, P. Pyrrolotriazines as potassium ion channel inhibitors. World Patent WO2014143610A1., 2014.
[130]
Demnitz, J.; Jorgensen, S. Novel tetrazole derivatives and their use as potassium chan-nel modulators. World Patent WO2014001363A1., 2014.
[131]
Chen, H.; Liang, B.; Zhao, Z.; Cao, W.; Xu, W.; Li, Q.; Wang, J. Compound as potassium channel modulator. World Patent WO2014048165A1., 2014.
[132]
Minor, D.R., Jr; Bagriantsev, S.N.; Renslo, A.R. Modulation of k2p channels. World Patent WO2014165307A2., 2014.
[133]
Lanter, J.C.; Sui, Z. 3,4-diamino-3-cyclobutene-1,2-dione derivatives as potassi-um channel openers. Eur Patent EP2010509 B1., 2014.
[134]
Brown, B.S.; Li, T.; Peddi, S.; Perez-Medrano, A.; DeGoey, D. Potassium channel modulators. US Patent US8629143B2., 2014.
[135]
Liu, J.O.; Ren, Y.; Pan, F.; Chong, C.R.; Penner, R.; Behr, J.R. Phenazine derivatives and uses thereof as potassium channel modulators. US Patent US8669257B2., 2014.
[136]
Sørensen, U.S.; Eriksen, B.L.; Hougaard, C.; Strøbæk, D.; Christophersen, P. Substituted [1,2,4]triazolo[1,5-a]pyrimidines and their use as potassium channel modulators. US Patent US8685987B2., 2014.
[137]
Brown, B.S.; Li, T.; Peddi, S.; Perez-Medrano, A.; DeGoey, D. Potassium channel modulators. US Patent US8859549B2., 2014.
[138]
Sorensen, U.S.; Eriksen, B.L.; Charlotte, H.; Strobek, D.; Christophersen, P. Substituted [1,2,4]triazolo[1,5-a]pyrimidines and their use as potassium channel modulators. US Patent US8765770B2., 2014.
[139]
Attali, B.; Peretz, A. N-phenyl anthranilic acid derivatives and uses thereof. US Patent US8765815B2., 2014.
[140]
Vernier, J.M.; Song, J.; Chen, H.; Hong, Z. N-[2-amino-4- (phenylmethoxy)phenyl] amides and related compounds as potassium channel modulators. US Patent US8722929B2., 2014.
[141]
Tang, H.; Pio, B.; Jiang, J.; Pasternak, A.; Dong, S.; Ferguson, R.D.; Guo, Z.Z.; Chobanian, H.; Frie, J.; Guo, Y.; Wu, Z.; Yu, Y.; Wang, M. Inhibitors of the renal outer medullary potassium channel. World Patent, WO2015017305A1., 2015.
[142]
Mccabe, B.D. 4-aminopyridine as a therapeutic agent for spinal muscular atrophy. US Patent US20150064234A1., 2015.
[143]
Scanio, M.J.; Bunnelle, W.H.; Carroll, W.A.; Peddi, S.; Perez-Medrano, A.; Shi, L. Potassium channel modulators. US Patent US8962639B2., 2015.
[144]
Ford, J.; Madge, D.J.; Payne, H.J.; Knight, J.D. Thieno [3,2-c] pyridine potassium channel inhibitors. US Patent US9216992B2., 2015.
[145]
Alvaro, G.; Decor, A.; Fontana, S.; Hamprecht, D.; Large, C.; Marasco, A. Imidazolidinedione derivatives. US Patent US9216967B2., 2015.
[146]
Vernier, J.M.; De La Rosa, M.A.; Chen, H.; Wu, J.Z.; Larson, G.L.; Cheney, I.W.N. N-(4-(6-fluoro-3, 4-dihydroisoquinolin-2 (1H)-yl)-2, 6-dimethylphenyl)-3, 3-dimethylbutanamide as potassium channel modulators. US Patent US8993593B2., 2015.
[147]
Weaver, C.D. Vanderbilt University, 2015. Compound, composition, and method of activating GIRK potassium channel and use of same for treating conditions of interest. US Patent US9067894B1., 2015.
[148]
Alvaro, G.; Marasco, A. Compounds. US Patent US9133175B2., 2015.
[149]
Tang, H.; Pio, B.; Chobanian, H.R. Inhibitors of the renal outer medullary potassium channel. US Patent US8999991B2., 2015.
[150]
Kühnert, S.; Bahrenberg, G.; Kless, A.; Schröder, W. Substituted 2-oxy-quinoline-3-carboxamides as KCNQ2/3 modulators. US Patent US9073862B2., 2015.
[151]
Ishihara, T.; Ikegai, K.; Kuriwaki, I.; Hisamichi, H.; Takeshita, N.; Takezawa, R. Benzothiophene compound. US Patent US8981119B2., 2015.
[152]
Minor, D.L.; Bagriantsev, S.N.; Renslo, A.R. Modulation of k2p channels. US Patent US20160031814A1., 2015.
[153]
Edwards, S.D.; Kimberley, M.R.; Armer, R.E.; Khan, N.M. Potassium ion channel modulators and uses thereof. US Patent US9464052B2., 2016.
[154]
Eriksen, B.L.; Sørensen, U.S.; Hougaard, C.; Peters, D.; Johansen, T.H.; Christophersen, P. Purinyl derivatives and their use as potassium channel modulators. US Patent US9340544B2., 2016.
[155]
Mulla, M.; John, D.E.; Hamlyn, R.J.; Garrett, S.L.; Hartzoulakis, B.; Madge, D.; Ford, J. Potassium channel blockers. US Patent US9447033B2., 2016.
[156]
Attali, B.; Peretz, A. N-phenyl anthranilic acid derivatives and uses thereof. US Patent US9403756B2., 2016.
[157]
Harvey, A.; Bombrun, A.; Cooke, R.; Jeanclaude-Etter, I.; Kuchel, N.; Molette, J.; Mould, J.; Paul, D.; Singh, R.; Donini, C.; Colovray, V. Amine derivatives as potassium channel blockers. US Patent US9493451B2., 2016.
[158]
Finlay, H.; Adisechan, A.K.; Gunaga, P.; Lloyd, J.; Pothukanuri, S. Pyrrolopyridazines as potassium ion channel inhibitors. US Patent US9458164B2., 2016.
[159]
Lucas, S.; Kühnert, S.; Bahrenberg, G.; Schröder, W. Specific carboxamides as KCNQ2/3 modulators. US Patent US9284286B2., 2016.
[160]
Madge, D.; Chan, F.; John, D.E.; Edwards, S.D.; Blunt, R.; Hartzoulakis, B.; Brown, L. Thieno-pyrimidines, useful as potassium channel inhibitors. . US Patent US9290511B2., 2016.
[161]
Kühnert, S.; Lucas, S.; Bahrenberg, G.; Schröder, W. Heteroquinoline- 3-carboxamides as KCNQ2/3 modulators. US Patent US9248122B2., 2016.
[162]
Resnick, L.; Topalov, G.T.; Boyd, S.A.; Belardi, J.K.; Flentge, C.A.; Hale, J.S.; Harried, S.S.; Mareska, D.A.; Zhang, K.; Heap, C.R.; Hadden, M. Imidazo[4, 5-b]pyridin-2-yl amides as kv7 channel activators. US Patent US20170240547A1., 2017.
[163]
Walsh, S.P.; Brian, C.; Jessica, L.F.; Dooseop, K.; Alexander, P.; Zhi-Cai, S. Inhibitors of the renal outer medullary potassium channel. US Patent US9777002B2., 2017.
[164]
Demnitz, J.; Susanne, J. Tetrazole derivatives and their use as potassium channel modulators. US Patent US9556132B2, 2017.
[165]
Edwards, S.; Kimberley, R.M.; Armer, R.E.; Khan, M.N. Potassium ion channel modulators and uses thereof. US Patent US9675567B2., 2017.
[166]
Alvaro, G.; Decor, A.; Fontana, S.; Hamprecht, D.; Large, C. Imidazolidinedione derivatives. US Patent US20170065585A1 ., 2017.
[167]
Edwards, D. S.; Askew, B.C.; Furuya, T. Fluorinated 2-amino- 4-(substituted amino)phenyl carbamate derivatives. World Patent WO2017214539A1., 2017.

Rights & Permissions Print Cite
Article Metrics
82
12
© 2024 Bentham Science Publishers | Privacy Policy