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.