Naslov
Macrolide inspired macrocycles as modulators of the IL- 17A/IL-17RA interaction

Autori
Koštrun, Sanja ; Fajdetić, Andrea ; Pešić, Dijana ; Brajša, Karmen ; Bencetić Mihaljević, Vlatka ; Jelić, Dubravko ; Petrinić Grba, Adriana ; Elenkov, Ivaylo ; Rupčić, Renata ; Kapić, Samra ; Ozimec Landek, Ivana ; Butković, Kristina ; Grgičević, Ana ; Žiher, Dinko ; Čikoš, Ana ; Padovan, Jasna ; Saxty, Gordon ; Duck, Kevin ; Bladh, Haakan ; Skak- Nielsen, Tine ; Feldbaek Nielsen, Simon ; Lambert, Maja ; Stahlhut, Martin

Izvornik
Journal of medicinal chemistry (0022-2623) 64 (2021), 12; 8354-8383

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
proteins ; macrocycles ; IL 17AM ; Il 17RA ; chemical structure inhibitors

Sažetak
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.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Temeljne medicinske znanosti, Interdisciplinarne biotehničke znanosti

POVEZANOST RADA