Exploration of the chemical space of benzamide-based voltage-gated potassium channel Kv1.3 inhibitors

Fois, Marzia (author), Pelcar, Špela (author), Joshua A., Nasburg (author), Wulff, Heike (author), Peterlin-Mašič, Lucija (author), Tomašič, Tihomir (author)

The voltage-gated potassium channel K$_v$1.3 is a key regulator of T-cell activation and a validated therapeutic target for autoimmune and inflammatory diseases. In this study, a ligand-based design strategy was employed to expand a library of benzamide-derived K$_v$1.3 inhibitors. Starting from a previously optimised thiophene-based inhibitor, structural modifications were introduced to the 2-methoxybenzamide moiety and the central tetrahydropyran or cyclohexane scaffold. A series of ketone, hydroxy, and carbamate derivatives was synthesised and evaluated for K$_v$1.3 inhibition using whole-cell patch-clamp electrophysiology. Structure-activity relationship analysis revealed that cis-isomers in the hydroxy series exhibited stronger activity than their trans counterparts, with some analogues displaying submicromolar IC$^{50}$ values. In the carbamate series, trans-isomers were generally more potent, with trans-18 and trans-16 achieving IC$^{50}$ values of 122 and 166 nmol L$^{-1}$, respectively. These results provide valuable insights into the design of K$_v$1.3 inhibitors and support further development of these compounds for immunomodulatory applications.

• Language: English
• Keywords: Kv1.3, inhibitor, ion channel, ligand-based design, molecular modeling
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2025
• Number of pages: Str. 219-233
• Numbering: Vol. 75, iss. 2
• PID: 20.500.12556/RUL-169975
• UDC: 616-097
• ISSN on article: 1846-9558
• DOI: 10.2478/acph-2025-0019
• COBISS.SI-ID: 240658691
• Publication date in RUL: 30.06.2025

Record is a part of a journal

• Title: Acta pharmaceutica
• Shortened title: Acta pharm.
• Publisher: Croatian Pharmaceutical Society
• ISSN: 1846-9558
• COBISS.SI-ID: 3817585

Licences

• License: CC BY-NC-ND 4.0, Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
• Link: http://creativecommons.org/licenses/by-nc-nd/4.0/
• Description: The most restrictive Creative Commons license. This only allows people to download and share the work for no commercial gain and for no other purposes.

Secondary language

• Language: Slovenian
• Keywords: avtoimunske bolezni, Kv1.3, inhibitorji, ionski kanali, zasnova na osnovi ligandov, molekularno modeliranje