Novartis Biomedical Research, Basel CH-4002, Switzerland.
J Med Chem. 2024 Sep 26;67(18):16692-16711. doi: 10.1021/acs.jmedchem.4c01520. Epub 2024 Sep 14.
IL-17, a pro-inflammatory cytokine produced mainly by Th17 cells, is involved in the immune response to fungal and bacterial infections, whereas its aberrant production is associated with autoimmune and inflammatory diseases. IL-17 blocking antibodies like secukinumab (Cosentyx) have been developed and are used to treat conditions like psoriasis, psoriatic arthritis, and ankylosing spondylitis. Recently, the low molecular weight IL-17 inhibitor LY3509754 entered the clinic but was discontinued in Phase 1 due to adverse effects. In this study, we explored the replacements of furazan moiety posing a potential toxicology risk in LY3509754. By exploring replacements such as heterocycles as amide-isosteres as well as α-F-acrylamides, two compounds ( and ) were identified. Both compounds effectively reduced knee swelling in a rat arthritis model. However, early rat and dog toxicity studies revealed adverse findings, preventing their further development and indicating that furazan might not be responsible for the adverse effects of LY3509754.
IL-17 是一种促炎细胞因子，主要由 Th17 细胞产生，参与对真菌和细菌感染的免疫反应，而其异常产生与自身免疫和炎症性疾病有关。已经开发出了像司库奇尤单抗（Cosentyx）这样的 IL-17 阻断抗体，并用于治疗银屑病、银屑病关节炎和强直性脊柱炎等疾病。最近，低分子量的 IL-17 抑制剂 LY3509754 进入了临床阶段，但由于不良反应在 1 期临床试验中被终止。在这项研究中，我们探讨了 LY3509754 中存在的可能具有毒理学风险的呋咱基团的替代品。通过探索酰胺等杂环作为酰胺等类似物以及 α-F-丙烯酰胺的替代品，鉴定出了两种化合物（ 和 ）。这两种化合物都能有效减轻大鼠关节炎模型中的膝关节肿胀。然而，早期的大鼠和狗毒性研究发现了不良发现，阻止了它们的进一步开发，并表明呋咱可能不是 LY3509754 不良反应的原因。
