Development of novel kv1.3 ion channel blockers based upon diphenoxylate

Psoriasis is an autoimmune disorder of the skin that affects millions of people worldwide. Current treatments have limitations concerning their efficacy, side effect profiles and cost. The need for better treatments is clear and our research is aimed at developing a novel therapy for psoriasis with an improved profile. Previous research has shown that a drug normally used for diarrhoea (diphenoxylate) was able to treat psoriasis; however this important observation was not fully evaluated. Our preliminary work has demonstrated that diphenoxylate blocks a key potassium channel (Kv1.3) associated with the immune system. Indeed, Kv1.3 channels have been shown to have a role in autoimmune disorders such as psoriasis and may explain the observations that diphenoxylate was able to treat psoriasis. Our initial research has generated novel analogues of diphenoxylate to explore the SAR of this molecule at Kv1.3 channels. Further synthetic work has built on this initial SAR to generate compounds that are over 100 times more potent at Kv1.3 channels than our original lead, diphenoxylate. In addition these potent Kv1.3 blockers are lower in molecular weight and have reduced lipophilicity While providing a potential explanation for the observation that diphenoxylate alleviates psoriasis symptoms, many new chemotypes were also produced that block Kv1.3 channels. A selected number of these interesting leads will be progressed into functional assays to further assess their immunomodulatory activity. Ultimately, this work has provided new opportunities for the development of novel treatments that target autoimmune disorders.