New aryl and acylsulfonamides as state-dependent inhibitors of Na$_v$1.3 voltage-gated sodium channel

Zidar, Nace (author), Tomašič, Tihomir (author), Kikelj, Danijel (author), Durcik, Martina (author), Tytgat, Jan (author), Peigneur, Steve (author), Rogers, Marc (author), Haworth, Alexander (author), Kirby, Robert W. (author)

Voltage-gated sodium channels (Na$_v$s) play an essential role in neurotransmission, and their dysfunction is often a cause of various neurological disorders. The Na$_v$1.3 isoform is found in the CNS and upregulated after injury in the periphery, but its role in human physiology has not yet been fully elucidated. Reports suggest that selective Na$_v$1.3 inhibitors could be used as novel therapeutics to treat pain or neurodevelopmental disorders. Few selective inhibitors of this channel are known in the literature. In this work, we report the discovery of a new series of aryl and acylsulfonamides as state-dependent inhibitors of Na$_v$1.3 channels. Using a ligand-based 3D similarity search and subsequent hit optimization, we identified and prepared a series of 47 novel compounds and tested them on Na$_v$1.3, Na$_v$1.5, and a selected subset also on Na$_v$1.7 channels in a QPatch patch-clamp electrophysiology assay. Eight compounds had an IC$_{50}$ value of less than 1 μM against the Na$_v$1.3 channel inactivated state, with one compound displaying an IC$_{50}$ value of 20 nM, whereas activity against the inactivated state of the Na$_v$1.5 channel and Na$_v$1.7 channel was approximately 20-fold weaker. None of the compounds showed usedependent inhibition of the cardiac isoform Na$_v$1.5 at a concentration of 30 μM. Further selectivity testing of the most promising hits was measured using the two-electrode voltage-clamp method against the closed state of the Na$_v$1.1-Na$_v$1.8 channels, and compound 15b displayed small, yet selective, effects against the Na$_v$1.3 channel, with no activity against the other isoforms. Additional selectivity testing of promising hits against the inactivated state of the Na$_v$1.3, Na$_v$1.7, and Na$_v$1.8 channels revealed several compounds with robust and selective activity against the inactivated state of the Na$_v$1.3 channel among the three isoforms tested. Moreover, the compounds were not cytotoxic at a concentration of 50 μM, as demonstrated by the assay in human HepG2 cells (hepatocellular carcinoma cells). The novel state-dependent inhibitors of Na$_v$1.3 discovered in this work provide a valuable tool to better evaluate this channel as a potential drug target.

• Language: English
• Keywords: voltage-gated sodium channel, Na$_v$ channel, Na$_v$1.3, inhibitor, arylsulfonamide, acylsulfonamide
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2023
• Number of pages: 23 str.
• Numbering: Vol. 258, art. 115530
• PID: 20.500.12556/RUL-148297-4944731f-ea9d-93d7-cf75-5972bc0d0f2e
• UDC: 615.4:54:616.8
• ISSN on article: 0223-5234
• DOI: 10.1016/j.ejmech.2023.115530
• COBISS.SI-ID: 156075779
• Publication date in RUL: 10.08.2023

ZIDAR, Nace, TOMAŠIČ, Tihomir, KIKELJ, Danijel, DURCIK, Martina, TYTGAT, Jan, PEIGNEUR, Steve, ROGERS, Marc, HAWORTH, Alexander and KIRBY, Robert W., 2023, New aryl and acylsulfonamides as state-dependent inhibitors of Na$_v$1.3 voltage-gated sodium channel. European journal of medicinal chemistry [online]. 2023. Vol. 258,  115530. [Accessed 15 April 2025]. DOI 10.1016/j.ejmech.2023.115530. Retrieved from: https://repozitorij.uni-lj.si/IzpisGradiva.php?lang=eng&id=148297

Record is a part of a journal

• Title: European journal of medicinal chemistry
• Shortened title: Eur. j. med. chem.
• Publisher: Elsevier
• ISSN: 0223-5234
• COBISS.SI-ID: 25429760

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: napetostno odvisni natrijev kanal, Na$_v$ kanal, Na$_v$1.3, zaviralci, arilsulfonamid, acilsulfonamid, nevrologija, farmacevtska kemija