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
  • 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.