Discovery and In Vivo Exploration of 1,3,4-Oxadiazole and α-Fluoroacrylate Containing IL-17 Inhibitors,Journal of Medicinal Chemistry

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Discovery and In Vivo Exploration of 1,3,4-Oxadiazole and α-Fluoroacrylate Containing IL-17 Inhibitors
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-09-14 , DOI: 10.1021/acs.jmedchem.4c01520
Juraj Velcicky ₁ , Matthias R Bauer ₁ , Achim Schlapbach ₁ , Guillaume Lapointe ₁ , Arndt Meyer ₁ , Markus Vögtle ₁ , Ernst Blum ₁ , Estelle Ngo ₁ , Catherine Rolando ₁ , Pierre Nimsgern ₁ , Sylvie Teixeira-Fouchard ₁ , Hansjoerg Lehmann ₁ , Pascal Furet ₁ , Frédéric Berst ₁ , Jens Schümann ₁ , Rowan Stringer ₁ , Patrice Larger ₁ , Cindy Schmid ₁ , Catriona T Prendergast ₁ , Simone Riek ₁ , Patrick Schmutz ₁ , Sylvie Lehmann ₁ , Jörg Berghausen ₁ , Clemens Scheufler ₁ , Jean-Michel Rondeau ₁ , Christoph Burkhart ₁ , Thomas Knoepfel ₁ , Nina Gommermann ₁

Affiliation

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 (18 and 26) 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.

中文翻译：

含 1,3,4-噁二唑和 α-氟丙烯酸酯的 IL-17 抑制剂的发现和体内探索

IL-17 是一种主要由 Th17 细胞产生的促炎细胞因子，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。已经开发出苏金单抗（Cosentyx）等 IL-17 阻断抗体，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 IL-17 抑制剂LY3509754进入临床，但由于不良反应在 1 期停药。在这项研究中，我们探讨了在 LY3509754 中构成潜在毒理学风险的呋喃呋喃部分的替代。通过探索酰胺等等杂环以及 α-F-丙烯酰胺等替代品，鉴定出两种化合物（18 和 26）。这两种化合物都有效地减少了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揭示了不良发现，阻止了它们的进一步发展，并表明呋喃赞可能与LY3509754的不良反应无关。

更新日期：2024-09-14

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