20.500.12556/RUL-169975 Exploration of the chemical space of benzamide-based voltage-gated potassium channel Kv1.3 inhibitors 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. Kv1.3 inhibitor ion channel ligand-based design molecular modeling avtoimunske bolezni Kv1.3 inhibitorji ionski kanali zasnova na osnovi ligandov molekularno modeliranje true false true Angleški jezik Slovenski jezik Članek v reviji 2025-06-30 10:20:53 2025-06-30 10:20:58 2025-07-01 03:55:47 0000-00-00 00:00:00 2025 0 0 Str. 219-233 iss. 2 Vol. 75 2025 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 616-097 1846-9558 10.2478/acph-2025-0019 240658691 21925.pdf 21925.pdf 1 2F8B32FE9FD376076B9F543E1C9689D2 201a37fa53fcb991f71825e95a630dd8b8affffa499e0252b3b02e47fa455195 6c5658f3-558b-11f0-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=211858 https://acta.pharmaceutica.farmaceut.org/wp-content/uploads/2025/06/21925.pdf 1 42d9deb0-5589-11f0-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=211857 Fakulteta za farmacijo 0 0 0