Login Register Cart 0
Generic placeholder image

Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Review Article

Medicinal Chemistry of Potassium Channel Modulators: An Update of Recent Progress (2011-2017)

Author(s): Vivek K. Vyas*, Palak Parikh, Jonali Ramani and Manjunath Ghate

Volume 26, Issue 12, 2019

Page: [2062 - 2084] Pages: 23

DOI: 10.2174/0929867325666180430152023

Price: $65

conference banner
Abstract

Background: Potassium (K+) channels participate in many physiological processes, cardiac function, cell proliferation, neuronal signaling, muscle contractility, immune function, hormone secretion, osmotic pressure, changes in gene expression, and are involved in critical biological functions, and in a variety of diseases. Potassium channels represent a large family of tetrameric membrane proteins. Potassium channels activation reduces excitability, whereas channel inhibition increases excitability.

Objective: Small molecule K+ channel activators and inhibitors interact with voltage-gated, inward rectifying, and two-pore tandem potassium channels. Due to their involvement in biological functions, and in a variety of diseases, small molecules as potassium channel modulators have received great scientific attention.

Methods: In this review, we have compiled the literature, patents and patent applications (2011 to 2017) related to different chemical classes of potassium channel openers and blockers as therapeutic agents for the treatment of various diseases. Many different chemical classes of selective small molecule have emerged as potassium channel modulators over the past years.

Conclusion: This review discussed the current understanding of medicinal chemistry research in the field of potassium channel modulators to update the key advances in this field.

Keywords: Potassium channel modulators, potassium channel openers, potassium channel blockers, ATP-sensitive potassium channels, voltage-gated potassium channels, inward rectifying potassium channels.

« 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
118
13
Wayfinder Image
World Antimicrobial Awareness Week
© 2024 Bentham Science Publishers | Privacy Policy