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

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

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.

• Jezik: Angleški jezik
• Ključne besede: Kv1.3, inhibitor, ion channel, ligand-based design, molecular modeling
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2025
• Št. strani: Str. 219-233
• Številčenje: Vol. 75, iss. 2
• PID: 20.500.12556/RUL-169975
• UDK: 616-097
• ISSN pri članku: 1846-9558
• DOI: 10.2478/acph-2025-0019
• COBISS.SI-ID: 240658691
• Datum objave v RUL: 30.06.2025

Gradivo je del revije

• Naslov: Acta pharmaceutica
• Skrajšan naslov: Acta pharm.
• Založnik: Croatian Pharmaceutical Society
• ISSN: 1846-9558
• COBISS.SI-ID: 3817585

Licence

• Licenca: CC BY-NC-ND 4.0, Creative Commons Priznanje avtorstva-Nekomercialno-Brez predelav 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by-nc-nd/4.0/deed.sl
• Opis: Najbolj omejujoča licenca Creative Commons. Uporabniki lahko prenesejo in delijo delo v nekomercialne namene in ga ne smejo uporabiti za nobene druge namene.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: avtoimunske bolezni, Kv1.3, inhibitorji, ionski kanali, zasnova na osnovi ligandov, molekularno modeliranje