9h4o
Crystal structure of IL-17A in complex with compound 11
Structural highlights
FunctionIL17_HUMAN Induces stromal cells to produce proinflammatory and hematopoietic cytokines. Enhances the surface expression of ICAM1/intracellular adhesion molecule 1 in fibroblasts. Publication Abstract from PubMedThe 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((R))). 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. Thiazole-Based IL-17 Inhibitors Discovered by Scaffold Morphing.,Velcicky J, Ngo E, Bauer MR, Meyer A, Schlapbach A, Racine S, Orain D, Pflieger D, Teixeira-Fouchard S, Dubois C, Goetz A, Steiner R, Palmieri M, Bussenault A, Stringer R, Larger P, Riek S, Schmutz P, Lehmann S, Scheufler C, Rondeau JM, Burkhart C, Knoepfel T, Gommermann N ChemMedChem. 2024 Dec 23:e202400851. doi: 10.1002/cmdc.202400851. PMID:39715021[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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