Efficient Regioselective Synthesis of Benzimidazoles and Azabenz­imidazoles to Enable the Rapid Development of Structure–Activity Relationships for Activation of SLACK Potassium Channels

Abstract

The sodium-activated potassium channel known as SLACK (K_Na1.1 or Slo2.2) is widely expressed in the central nervous system and represents a potential target for the treatment of several neurological disorders. While much recent progress has been made toward the discovery of small-molecule inhibitors of these channels, reports regarding small-molecule activators have been scant. Having identified such compounds via a high-throughput screen, we were interested in establishing structure–activity relationships that could serve as the foundation for the design of potent activators of SLACK channels. In this letter, we describe the implementation of an efficient synthetic approach to the regioselective synthesis of a series of benzimidazole and azabenzimidazoles based on one of our hit compounds. The key step utilizes a one-pot reduction/formylation/condensation reaction of 2-nitro-arylamines. Also presented herein are the functional activities for 15 new analogues prepared by this approach and obtained via a thallium-flux assay in cells stably expressing human wild-type SLACK channels. Many of these new analogues demonstrate substantially improved potency relative to the initial hit compound and provide valuable new data that can be utilized in the design of additional derivatives.

Key words

SLACK - K_Na1.1 - Slo2.2 - potassium channel - benzimidazoles

Publikationsverlauf

Eingereicht: 28. Februar 2025

Angenommen nach Revision: 10. April 2025

Accepted Manuscript online:
14. April 2025

Artikel online veröffentlicht:
23. Mai 2025

• References

• 1 Current Address: Biohaven Pharmaceuticals, Inc., 2100 Wharton Street, Suite 615, Pittsburgh, PA 15203, USA.
• 2 Current Address: Baylor Scott & White Medical Center, 1901 N. MacArthur Blvd., Irving, TX, 75061, USA.
• 3 Kaczmarek LK. ISRN Neuroscience 2013; 2013: 1
• 4 Yuan A, Santi CM, Wei A, Wang ZW, Pollak K, Nonet M, Kaczmarek L, Crowder CM, Salkoff L. Neuron 2003; 37: 765
• 5 Bhattacharjee A, Gan L, Kaczmarek LK. J. Comp. Neurol. 2002; 454: 241
• 6 Bonardi CM, Heyne HO, Fiannacca M, Fitzgerald MP, Gardella E, Gunning B, Olofsson K, Lesca G, Verbeek N, Stamberger H, Striano P, Zara F, Mancardi MM, Nava C, Syrbe S, Buono S, Baulac S, Coppola A, Weckhuysen S, Schoonjans A.-S, Ceulemans B, Sarret C, Baumgartner T, Muhle H, des Portes V, Toulouse J, Nougues M.-C, Rossi M, Demarquay G, Ville D, Hirsch E, Maurey H, Willems M, de Bellescize J, Altuzarra CD, Villeneuve N, Bartolomei F, Picard F, Hornemann F, Koolen DA, Kroes HY, Reale C, Fenger CD, Tan W.-H, Dibbens L, Bearden DR, Møller RS, Rubboli G. Brain 2021; 144: 3635
• 7 Barcia G, Chemaly N, Kuchenbuch M, Eisermann M, Gobin-Limballe S, Ciorna V, Macaya A, Lambert L, Dubois F, Doummar D, Billette de Villemeur T, Villeneuve N, Barthez M.-A, Nava C, Boddaert N, Kaminska A, Bahi-Buisson N, Milh M, Auvin S, Bonnefont J.-P, Nabbout R. Neurol. Genet. 2019; 5: e363
• 8 McTague A, Nair U, Malhotra S, Meyer E, Trump N, Gazina EV, Papandreou A, Ngoh A, Ackermann S, Ambegaonkar G, Appleton R, Desurkar A, Eltze C, Kneen R, Kumar AV, Lascelles K, Montgomery T, Ramesh V, Samanta R, Scott RH, Tan J, Whitehouse W, Poduri A, Scheffer IE, Chong WK, Cross JH, Topf M, Petrou S, Kurian MA. Neurology 2018; 90: e55
• 9 Barcia G, Fleming MR, Deligniere A, Gazula VR, Brown MR, Langouet M, Chen H, Kronengold J, Abhyankar A, Cilio R, Nitschke P, Kaminska A, Boddaert N, Casanova J.-L, Desguerre I, Munnich A, Dulac O, Kaczmarek LK, Colleaux L, Nabbout R. Nat. Genet. 2012; 44: 1255
• 10 Rizzo F, Ambrosino P, Guacci A, Chetta M, Marchese G, Rocco T, Soldovieri MV, Manocchio L, Mosca I, Casara G, Vecchi M, Taglialatela M, Coppola G, Weisz A. Mol. Cell. Neurosci. 2016; 72: 54
• 11 Tang QY, Zhang FF, Xu J, Wang R, Chen J, Logothetis DE, Zhang Z. Cell Rep. 2016; 14: 129
• 12 Moller RS, Heron SE, Larsen LH, Lim CX, Ricos MG, Bayly MA, van Kempen MJ, Klinkenberg S, Andrews I, Kelley K, Ronen GM, Callen D, McMahon JM, Yendle SC, Carvill GL, Mefford HC, Nabbout R, Poduri A, Striano P, Baglietto MG, Zara F, Smith NJ, Pridmore C, Gardella E, Nikanorova M, Dahl HA, Gellert P, Scheffer IE, Gunning B, Kragh-Olsen B, Dibbens LM. Epilepsia 2015; 56: e114
• 13 Heron SE, Smith KR, Bahlo M, Nobili L, Kahana E, Licchetta L, Oliver KL, Mazarib A, Afawi Z, Korczyn A, Plazzi G, Petrou S, Berkovic SF, Scheffer IE, Dibbens LM. Nat. Genet. 2012; 44 1188
• 14 Di Matteo F, Mancuso F, Turcio R, Ciaglia T, Stagno C, Di Chio C, Campiglia P, Bertamino A, Giofre SV, Ostacolo C, Iraci N. Molecules 2024; 29: 2940
• 15 Qunies AM, Emmitte KA. Pharm. Pat. Anal. 2022; 11: 45
• 16 Cole BA, Clapcote SJ, Muench SP, Lippiat JD. Trends Pharmacol. Sci. 2021; 42: 700
• 17 Mishra NM, Spitznagel BD, Du Y, Mohamed YK, Qin Y, Weaver CD, Emmitte KA. Molecules 2024; 29: 5494
• 18 Iraci N, Carotenuto L, Ciaglia T, Belperio G, Di Matteo F, Mosca I, Carleo G, Giovanna Basilicata M, Ambrosino P, Turcio R, Puzo D, Pepe G, Gomez-Monterrey I, Soldovieri MV, Di Sarno V, Campiglia P, Miceli F, Bertamino A, Ostacolo C, Taglialatela M. J. Med. Chem. 2024; 67: 9124
• 19 Qunies AM, Spitznagel BD, Du Y, Peprah PK, Mohamed YK, Weaver CD, Emmitte KA. Molecules 2024; 29: 2437
• 20 Qunies AM, Spitznagel BD, Du Y, David Weaver C, Emmitte KA. Bioorg. Med. Chem. 2023; 95: 117487
• 21 Qunies AM, Mishra NM, Spitznagel BD, Du Y, Acuna VS, David Weaver C, Emmitte KA. Bioorg. Med. Chem. Lett. 2022; 76: 129013
• 22 Griffin AM, Kahlig KM, Hatch RJ, Hughes ZA, Chapman ML, Antonio B, Marron BE, Wittmann M, Martinez-Botella G. ACS Med. Chem. Lett. 2021; 12: 593
• 23 Spitznagel BD, Mishra NM, Qunies A aM, Prael FJ. III, Du Y, Kozek KA, Lazarenko RM, Denton JS, Emmitte KA, Weaver CD. ACS Chem. Neurosci. 2020; 11: 3658
• 24 Cole BA, Johnson RM, Dejakaisaya H, Pilati N, Fishwick CW. G, Muench SP, Lippiat JD. iScience 2020; 23: 101100
• 25 Ferron L. J. Physiol. 2016; 594: 5861
• 26 Bausch AE, Dieter R, Nann Y, Hausmann M, Meyerdierks N, Kaczmarek LK, Ruth P, Lukowski R. Learn. Mem. 2015; 22: 323
• 27 Kim GE, Kaczmarek LK. Front. Cell. Neurosci. 2014; 8: 209
• 28 Zhang Y, Brown MR, Hyland C, Chen Y, Kronengold J, Fleming MR, Kohn AB, Moroz LL, Kaczmarek LK. J. Neurosci. 2012; 32: 15318
• 29 Brown MR, Kronengold J, Gazula VR, Chen Y, Strumbos JG, Sigworth FJ, Navaratnam D, Kaczmarek LK. Nat. Neurosci. 2010; 13: 819
• 30 Mila M, Alvarez-Mora MI, Madrigal I, Rodriguez-Revenga L. Clin. Genet. 2018; 93: 197
• 31 Berry-Kravis EM, Lindemann L, Jonch AE, Apostol G, Bear MF, Carpenter RL, Crawley JN, Curie A, Des Portes V, Hossain F, Gasparini F, Gomez-Mancilla B, Hessl D, Loth E, Scharf SH, Wang PP, Von Raison F, Hagerman R, Spooren W, Jacquemont S. Nat. Rev. Drug Discovery 2018; 17: 280
• 32 Riley C, Mailick M, Berry-Kravis E, Bolen J. Pediatrics 2017; 139: S147
• 33 Kaufmann WE, Kidd SA, Andrews HF, Budimirovic DB, Esler A, Haas-Givler B, Stackhouse T, Riley C, Peacock G, Sherman SL, Brown WT, Berry-Kravis E. Pediatrics 2017; 139: S194
• 34 Hagerman RJ, Berry-Kravis E, Hazlett HC, Bailey DB. Jr, Moine H, Kooy RF, Tassone F, Gantois I, Sonenberg N, Mandel JL, Hagerman PJ. Nat. Rev. Dis. Primers 2017; 3: 17065
• 35 Grigsby J. Clin. Neuropsychol. 2016; 30: 815
• 36 Biton B, Sethuramanujam S, Picchione KE, Bhattacharjee A, Khessibi N, Chesney F, Lanneau C, Curet O, Avenet P. J. Pharmacol. Exp. Ther. 2012; 340: 706
• 37 Popovic D, Nuss P, Vieta E. Ann. Gen. Psychiatry 2015; 14: 15
• 38 Lu R, Bausch AE, Kallenborn-Gerhardt W, Stoetzer C, Debruin N, Ruth P, Geisslinger G, Leffler A, Lukowski R, Schmidtko A. J. Neurosci. 2015; 35: 1125
• 39 Balzulat A, Zhu WF, Flauaus C, Hernandez-Olmos V, Heering J, Sethumadhavan S, Dubiel M, Frank A, Menge A, Hebchen M, Metzner K, Lu R, Lukowski R, Ruth P, Knapp S, Müller S, Steinhilber D, Hänelt I, Stark H, Proschak E, Schmidtko A. Adv. Sci. 2024; 11: e2307237
• 40 Beacham DW, Blackmer T, O’Grady M, Hanson GT. J. Biomol. Screen. 2010; 15: 441
• 41 Weaver CD. Methods Mol. Biol. 2018; 1684: 105
• 42 Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Adv. Drug Delivery Rev. 2001; 46: 3
• 43 Kelder J, Grootenhuis PD, Bayada DM, Delbressine LP, Ploemen JP. Pharm. Res. 1999; 16: 1514
• 44 Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD. J. Med. Chem. 2002; 45: 2615
• 45 Gupta M, Lee HJ, Barden CJ, Weaver DF. J. Med. Chem. 2019; 62: 9824
• 46 Ríos N, Chavarría C, Gil C, Porcal W. J. Heterocycl. Chem. 2013; 50: 720
• 47 Mueller R, Reddy V, Nchinda AT, Mebrahtu F, Taylor D, Lawrence N, Tanner L, Barnabe M, Eyermann CJ, Zou B, Kondreddi RR, Lakshminarayana SB, Rottmann M, Street LJ, Chibale K. ACS Omega 2020; 5: 6967
• 48 Brooks CA, Barton LS, Behm DJ, Eidam HS, Fox RM, Hammond M, Hoang TH, Holt DA, Hilfiker MA, Lawhorn BG, Patterson JR, Stoy P, Roethke TJ, Ye G, Zhao S, Thorneloe KS, Goodman KB, Cheung M. ACS Med. Chem. Lett. 2019; 10: 1228
• 49 Garrido A, Lepailleur A, Mignani SM, Dallemagne P, Rochais C. Eur. J. Med. Chem. 2020; 195: 112290
• 50 Arnott JA, Planey SL. Expert Opin. Drug Discovery 2012; 7: 863
• 51 Jamieson C, Moir EM, Rankovic Z, Wishart G. J. Med. Chem. 2006; 49: 5029
• 52 van de Waterbeemd H, Smith DA, Jones BC. J. Comput. Aided Mol. Des. 2001; 15: 273
• 53 Testa B, Crivori P, Reist M, Carrupt P.-A. Perspect. Drug Discovery Des. 2000; 19: 179