Velcicky, Juraj, Bauer, Matthias-1, Schlapbach, Achim, Lapointe, Guillaume, Meyer, Arndt, Voegtle, Markus, Blum, Ernst, Ngo, Estelle, Rolando, Catherine, Nimsgern, Pierre, Teixeira-Fouchard, Sylvie, Lehmann, Hansjoerg, Berst, Frederic, Schuemann, Jens, Stringer, Rowan, Larger, Patrice, Schmid, Cindy, Paape, Catriona, Riek, Simone, Schmutz, Patrick, Berghausen, Joerg, Scheufler, Clemens, Burkhart, Christoph, Knoepfel, Thomas, Gommermann, Nina, Furet, Pascal, Lehmann, Sylvie and Rondeau, Jean-Michel (2024) Discovery and in vivo exploration of 1,3,4-oxadiazole and α-fluoroacrylate containing IL-17 inhibitors. Journal of Medicinal Chemistry, 67 (18). pp. 16692-16711. ISSN 0022-26231520-4804

Abstract

IL-17 is a pro-inflammatory cytokine produced mainly by Th17 cells that is involved in the immune response to fungal and bacterial infections whereas aberrant production of IL-17 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. The use of heterocycles as amide-isosteres as well as α-F-acrylamides led to the discovery of compounds 15, 18 and 26. All three compounds showed a robust inhibition of knee swelling in a rat model of arthritis. Adverse findings were observed when testing 18 and 26 in early rat and/or dog toxicity studies, preventing their further development.

Item Type:	Article
Keywords:	IL-17, pharmacology, toxicology, fluoroacrylate, amide isostere, x-ray, Rescoss
Date Deposited:	12 Oct 2024 00:45
Last Modified:	12 Oct 2024 00:45
URI:	https://oak.novartis.com/id/eprint/54437