Design and characterization of a novel structural class of Kv1.3 inhibitors.

The voltage-gated potassium channel K1.3 is involved in multiple autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, diabetes mellitus type 1 and psoriasis. In many auto-immune diseases better treatment options are desired as existing therapies are often ineffective or become less effective over time, for which K1.3 inhibitors arise as promising candidates. In this study, five compounds were selected based on a 3D similarity searching methodology and subsequently screened ex vivo on the K1.3 channel. The screening resulted in two compounds inhibiting the K1.3 channel, of which TVS-12 was the most potent compound, while TVS-06 -although less potent- showed an excellent selectivity for K1.3. For both compounds the mechanism of action was investigated by an electrophysiological characterization on the K1.3 channel and three K1.3 mutants, designed to resemble the pore region of K1.2 channels. Structurally, the presence of a benzene ring and/or an oxane ring seems to cause a better interaction with the K1.3 channel, resulting in a 20-fold higher potency for TVS-12.