The voltage-gated potassium channel Kv1.3 represents a promising target for the treatment of autoimmune diseases like multiple sclerosis, rheumatoid arthritis and psoriasis as it is a crucial player in maintaining the activation signal within T-cells, potentially allowing for a selective suppression of autoimmunity and thus minimizing the potential for opportunistic infections during therapy. The Lead Optimization Program for two small mol. hit classes resulted in a fine-tuning of activity, selectivity and physicochem. and PK properties. Selected representatives display highly encouraging ameliorative effects within a set of animal models relevant in the context of autoimmune diseases, comparable or even favorable over pos. controls like methotrexate, betamethasone or tacrolimus. Based on promising PK/PD data, IND enabling studies shall be initiated.