Discovery and <i>In Vivo</i> Exploration\nof 1,3,4-Oxadiazole and α‑Fluoroacrylate Containing IL-17\nInhibitors

IL-17, a pro-inflammatory cytokine produced mainly by\nTh17 cells,\nis involved in the immune response to fungal and bacterial infections,\nwhereas its aberrant production is associated with autoimmune and\ninflammatory diseases. IL-17 blocking antibodies like secukinumab\n(Cosentyx) have been developed and are used to treat conditions like\npsoriasis, psoriatic arthritis, and ankylosing spondylitis. Recently,\nthe low molecular weight IL-17 inhibitor LY3509754 entered the clinic\nbut was discontinued in Phase 1 due to adverse effects. In this study,\nwe explored the replacements of furazan moiety posing a potential\ntoxicology risk in LY3509754. By exploring replacements such as heterocycles\nas amide-isosteres as well as α-F-acrylamides, two compounds\n(<b>18</b> and <b>26</b>) were identified. Both compounds\neffectively reduced knee swelling in a rat arthritis model. However,\nearly rat and dog toxicity studies revealed adverse findings, preventing\ntheir further development and indicating that furazan might not be\nresponsible for the adverse effects of LY3509754.