Design and synthesis of novel small molecules targeting the Kv1.3 voltage-gated potassium ion channel

Autoimmune diseases (ADs) affect almost 10% of the world population. They are also the leading cause of mortality among young and middle-aged women. Despite the available of therapeutic agents there is no definitive cure. The voltage-gated potassium channel (Kv1.3) plays a key role regulating various physiological processes, particularly immune responses, making it a promising target for immunomodulators. Moreover, the ability of Kv1.3 blockers to selectively modulate the activation of effector memory T-cells, without affecting other lymphoid subsets, make it a promising target to avoid fatal opportunistic infections encountered with broad spectrum immunosuppressants. Herein, a β-carboline-based lead (KMA) was developed through ligand-directed scaffold hopping based on the known Kv1.3 inhibitors, pyranoquinolinone and CP-339,818. Iterative structural derivatization and scaffold hopping produced piperidine and the hybrid analogs based on scaffolds of the potent Kv1.3 small inhibitors, UK-78,282 and PAP-1. Our biological assays produced two promising compounds; β-carboline-based (5c) and hybrid (13a). Notably, the hybrid compound 13a showed promising activity in relation to the Centruroides margaritatus scorpion short-chain toxin, margatoxin, which was used as positive control standard. Only compound 13a managed to decrease the Kv1.3 peak current amplitude by more than 80%, suggesting its viability as a lead compound for further investigations targeting ADs.

Keywords: Q3 2025