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      Kv1.3 inhibitors: en route to clinical trials

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      autoimmune diseases, Kv1.3 inhibitors, selective immunosuppression, autoreactive T-cells

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          Abstract

          The voltage-gated potassium channel Kv1.3 represents a promising target for the treatment of autoimmune diseases like multiple sclerosis, rheumatoid arthritis, uveitis and psoriasis as it is a crucial player in maintaining the activation signal within T-cells, allowing for a selective suppression of autoimmunity and thus minimizing the potential for opportunistic infections during therapy. The Lead Optimization Program for two small molecule hit classes resulted in a fine-tuning of activity, selectivity and physicochemical 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 favourable over positive controls like methotrexate, betamethasone or tacrolimus. Such inhibitors showed excellent tolerability in rats upon oral treatment with high doses for up to a month, had no effect on haematology and clinical biochemistry parameters and did not affect cells of the innate immunity or naive T-cells, clearly emphasizing their unique selling point, which is a highly specific immunosuppression of autoreactive T-cells.

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          10.14293/P2199-8442.1.SOP-CHEM.PDKXFG.v1

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