2. Academic Validation
  3. Discovery and In Vivo Exploration of 1,3,4-Oxadiazole and α-Fluoroacrylate Containing IL-17 Inhibitors

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

  • J Med Chem. 2024 Sep 26;67(18):16692-16711. 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
Affiliations

Affiliation

  • 1 Novartis Biomedical Research, Basel CH-4002, Switzerland.
PMID: 39276085 DOI: 10.1021/acs.jmedchem.4c01520
Abstract

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.

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