1. Macrolide Inspired Macrocycles as Modulators of the IL-17A/IL-17RA Interaction
- Author
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Ivaylo Jivkov Elenkov, Simon Feldbaek Nielsen, Kristina Butković, Sanja Koštrun, Dijana Pesic, Dack Kevin Neil, Tine Skak-Nielsen, Dinko Žiher, Martin Stahlhut, Adriana Petrinić Grba, Vlatka Bencetić Mihaljević, Ana Čikoš, Samra Kapić, Andrea Fajdetić, Renata Rupčić, Gordon Saxty, Maja Lambert, Jasna Padovan, Ivana Ozimec Landek, Karmen Brajša, Dubravko Jelić, Haakan Bladh, and Ana Grgičević
- Subjects
Male ,Macrocyclic Compounds ,THP-1 Cells ,Anti-Inflammatory Agents ,01 natural sciences ,Inflammatory bowel disease ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,Immune system ,In vivo ,Psoriasis ,Drug Discovery ,medicine ,Animals ,Humans ,030304 developmental biology ,ADME ,0303 health sciences ,Receptors, Interleukin-17 ,Molecular Structure ,Chemistry ,Drug discovery ,Interleukin-17 ,medicine.disease ,0104 chemical sciences ,Molecular Docking Simulation ,proteins ,macrocycles ,IL 17AM ,Il 17RA ,chemical structure inhibitors ,010404 medicinal & biomolecular chemistry ,Rheumatoid arthritis ,Immunology ,Molecular Medicine ,Interleukin 17 ,Protein Binding - Abstract
Interleukin 17 (IL-17) cytokines promote inflammatory pathophysiology in many autoimmune diseases, including psoriasis, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. Such broad involvement of IL-17 in various autoimmune diseases makes it an ideal target for drug discovery. Psoriasis is a chronic inflammatory disease characterized by numerous defective components of the immune system. Significantly higher levels of IL-17A have been noticed in lesions of psoriatic patients, if compared to non-lesion parts. Therefore, this paper is focused on the macrolide inspired macrocycles as potential IL-17A/IL-17RA modulators and covers the molecular design, synthesis, and in vitro profiling. Macrocycles are designed to diversify and enrich chemical space through different ring sizes and a variety of three-dimensional shapes. Inhibitors in the nM range were identified in both target-based and phenotypic assays. In vitro ADME as well as in vivo PK properties are reported.
- Published
- 2021
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