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

Autor:	Velcicky J; Novartis Biomedical Research, Basel CH-4002, Switzerland., Bauer MR; Novartis Biomedical Research, Basel CH-4002, Switzerland., Schlapbach A; Novartis Biomedical Research, Basel CH-4002, Switzerland., Lapointe G; Novartis Biomedical Research, Basel CH-4002, Switzerland., Meyer A; Novartis Biomedical Research, Basel CH-4002, Switzerland., Vögtle M; Novartis Biomedical Research, Basel CH-4002, Switzerland., Blum E; Novartis Biomedical Research, Basel CH-4002, Switzerland., Ngo E; Novartis Biomedical Research, Basel CH-4002, Switzerland., Rolando C; Novartis Biomedical Research, Basel CH-4002, Switzerland., Nimsgern P; Novartis Biomedical Research, Basel CH-4002, Switzerland., Teixeira-Fouchard S; Novartis Biomedical Research, Basel CH-4002, Switzerland., Lehmann H; Novartis Biomedical Research, Basel CH-4002, Switzerland., Furet P; Novartis Biomedical Research, Basel CH-4002, Switzerland., Berst F; Novartis Biomedical Research, Basel CH-4002, Switzerland., Schümann J; Novartis Biomedical Research, Basel CH-4002, Switzerland., Stringer R; Novartis Biomedical Research, Basel CH-4002, Switzerland., Larger P; Novartis Biomedical Research, Basel CH-4002, Switzerland., Schmid C; Novartis Biomedical Research, Basel CH-4002, Switzerland., Prendergast CT; Novartis Biomedical Research, Basel CH-4002, Switzerland., Riek S; Novartis Biomedical Research, Basel CH-4002, Switzerland., Schmutz P; Novartis Biomedical Research, Basel CH-4002, Switzerland., Lehmann S; Novartis Biomedical Research, Basel CH-4002, Switzerland., Berghausen J; Novartis Biomedical Research, Basel CH-4002, Switzerland., Scheufler C; Novartis Biomedical Research, Basel CH-4002, Switzerland., Rondeau JM; Novartis Biomedical Research, Basel CH-4002, Switzerland., Burkhart C; Novartis Biomedical Research, Basel CH-4002, Switzerland., Knoepfel T; Novartis Biomedical Research, Basel CH-4002, Switzerland., Gommermann N; Novartis Biomedical Research, Basel CH-4002, Switzerland.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Sep 26; Vol. 67 (18), pp. 16692-16711. Date of Electronic Publication: 2024 Sep 14.
DOI:	10.1021/acs.jmedchem.4c01520
Abstrakt:	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.
Databáze:	MEDLINE
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