Discovery and <i>In Vivo</i> Exploration of 1,3,4-Oxadiazole and α-Fluoroacrylate Containing IL-17 Inhibitors
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 (<b>18</b> and <b>26</b>) 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.
Authors
- Clemens Scheufler (ORCID: https://orcid.org/0000-0002-3693-3529)
- Sylvie Teixeira‐Fouchard
- Simone Riek
- Frédéric Berst (ORCID: https://orcid.org/0000-0002-6673-3915)
- Juraj Velcicky (ORCID: https://orcid.org/0000-0001-6564-1448)
- Nina Gommermann (ORCID: https://orcid.org/0000-0002-3684-4788)
- Thomas Knoepfel (ORCID: https://orcid.org/0000-0002-1675-6297)
- Cindy Schmid
- Ernst Blum
- Christoph Burkhart (ORCID: https://orcid.org/0000-0002-9014-4360)
- Guillaume Lapointe (ORCID: https://orcid.org/0000-0002-0451-0505)
- Patrice Larger (ORCID: https://orcid.org/0000-0002-4508-4741)
- Catriona T. Prendergast (ORCID: https://orcid.org/0000-0002-3777-5382)
- Jean‐Michel Rondeau (ORCID: https://orcid.org/0000-0003-0575-5480)
- Rowan Stringer (ORCID: https://orcid.org/0000-0002-8404-6107)
- Pierre Nimsgern
- Achim Schlapbach (ORCID: https://orcid.org/0000-0001-8137-8889)
- Hansjoerg Lehmann (ORCID: https://orcid.org/0000-0002-6239-7520)
- Matthias R. Bauer (ORCID: https://orcid.org/0000-0003-4015-6483)
- Arndt Meyer
- Jens Schümann
- E O Ngo
- Sylvie Lehmann
- Jörg Berghausen
- C. ROLANDO
- Patrick Schmutz
- Markus Vögtle
- Pascal Furet
Institutions
- Novartis (Switzerland) (CH)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-09-14
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01520
- Citations
- 6
- Primary Topic
- Psoriasis: Treatment and Pathogenesis
- Type
- article
- Field-Weighted Citation Impact
- 1.44
Funders
- Novartis Pharma