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. 2025 Apr 1;20(7):e202400851.
doi: 10.1002/cmdc.202400851. Epub 2025 Jan 12.

Thiazole-Based IL-17 Inhibitors Discovered by Scaffold Morphing

Juraj Velcicky  1 , Estelle Ngo  1 , Matthias R Bauer  1 , Arndt Meyer  1 , Achim Schlapbach  1 , Sophie Racine  1 , David Orain  1 , Daniel Pflieger  1 , Sylvie Teixeira-Fouchard  1 , Celine Dubois  1 , Alban Goetz  1 , Roland Steiner  1 , Marco Palmieri  1 , Alex Bussenault  1 , Rowan Stringer  1 , Patrice Larger  1 , Simone Riek  1 , Patrick Schmutz  1 , Sylvie Lehmann  1 , Clemens Scheufler  1 , Jean-Michel Rondeau  1 , Christoph Burkhart  1 , Thomas Knoepfel  1 , Nina Gommermann  1
Affiliations

Thiazole-Based IL-17 Inhibitors Discovered by Scaffold Morphing

Juraj Velcicky et al. ChemMedChem. .

Abstract

The pro-inflammatory cytokine interleukin-17A (IL-17) plays an important role in the body's defense against bacterial and fungal infections. However, overexpression of IL-17 has been associated with several diseases, including rheumatoid arthritis, asthma, psoriasis, and even cancer. The role of IL-17 in psoriasis has been confirmed by clinical use of IL-17 antibodies, e. g. secukinumab (Cosentyx®). Ongoing research is focused on discovering low molecular weight IL-17 inhibitors. In this publication, we present thiazole-based IL-17 inhibitors discovered through a scaffold-morphing strategy. This strategy involved ring-opening of a known scaffold and utilization of a chalcogen interaction between thiazole-sulfur and central amide-oxygen to maintain the coplanar conformation found in the parent compound. The new scaffold enabled the generation of highly potent compounds with good overall profile. The optimized compounds 11 and 15 demonstrated good exposure in rats after oral dosing. Importantly, compound 11 exhibited no adverse effects in a rat tolerability study after a four-day administration of up to 300 mg/kg/day.

Keywords: IL-17; Pharmacokinetic; Thiazole; X-Ray.

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