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

Abstract

The voltage-gated potassium channel K_v1.3 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 K_v1.3 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 K_v1.3 channel. The screening resulted in two compounds inhibiting the K_v1.3 channel, of which TVS-12 was the most potent compound, while TVS-06 -although less potent- showed an excellent selectivity for K_v1.3. For both compounds the mechanism of action was investigated by an electrophysiological characterization on the K_v1.3 channel and three K_v1.3 mutants, designed to resemble the pore region of K_v1.2 channels. Structurally, the presence of a benzene ring and/or an oxane ring seems to cause a better interaction with the K_v1.3 channel, resulting in a 20-fold higher potency for TVS-12.