Macrolide Inspired Macrocycles as Modulators of the IL-17A/IL-17RA Interaction
dataset
posted on 2021-06-08, 14:39 authored by Sanja Koštrun, Andrea Fajdetić, Dijana Pešić, Karmen Brajša, Vlatka Bencetić Mihaljević, Dubravko Jelić, Adriana Petrinić Grba, Ivaylo Elenkov, Renata Rupčić, Samra Kapić, Ivana Ozimec Landek, Kristina Butković, Ana Grgičević, Dinko Žiher, Ana Čikoš, Jasna Padovan, Gordon Saxty, Kevin Dack, Haakan Bladh, Tine Skak-Nielsen, Simon Feldbaek Nielsen, Maja Lambert, Martin StahlhutInterleukin 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.
