2. Academic Validation
  3. Macrolide Inspired Macrocycles as Modulators of the IL-17A/IL-17RA Interaction

Macrolide Inspired Macrocycles as Modulators of the IL-17A/IL-17RA Interaction

  • J Med Chem. 2021 Jun 24;64(12):8354-8383. doi: 10.1021/acs.jmedchem.1c00327.
Sanja Koštrun 1,  Andrea Fajdetić 1,  Dijana Pešić 1,  Karmen Brajša 1,  Vlatka Bencetić Mihaljević 1,  Dubravko Jelić 1,  Adriana Petrinić Grba 1,  Ivaylo Elenkov 1,  Renata Rupčić 1,  Samra Kapić 1,  Ivana Ozimec Landek 1,  Kristina Butković 1,  Ana Grgičević 1,  Dinko Žiher 1,  Ana Čikoš 1,  Jasna Padovan 1,  Gordon Saxty 1,  Kevin Dack 2,  Haakan Bladh 2,  Tine Skak-Nielsen 2,  Simon Feldbaek Nielsen 2,  Maja Lambert 2,  Martin Stahlhut 2
Affiliations

Affiliations

  • 1 Fidelta Ltd, Prilaz baruna Filipovića 29, 10000 Zagreb, Croatia.
  • 2 LEO Pharma A/S, Industriparken 55, 2750 Ballerup, Denmark.
PMID: 34100601 DOI: 10.1021/acs.jmedchem.1c00327
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.

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