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

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.

Discovery of an Oral, Rule of 5 Compliant, Interleukin 17A Protein–Protein Interaction Modulator for the Potential Treatment of Psoriasis and Other Inflammatory Diseases

“…When Ensemble 159 was profiled in a human epidermal keratinocyte (HEKa) assay, stimulated by IL-17A and TNFα to release the pro-inflammatory cytokine IL-8, a functional EC 50 of 151 nM at inhibiting IL-8 secretion was observed. To examine this finding further, LEO Pharma A/S entered into a partnership with Fidelta to explore alternative macrocyclic templates, including those based on azithromycin, and some of that work has been published …”

“…To examine this finding further, LEO Pharma A/S entered into a partnership with Fidelta to explore alternative macrocyclic templates, including those based on azithromycin, and some of that work has been published. 43 The joint research team tested intermediates to explore the SAR and the role of the macrocycle and, in doing so, identified nonmacrocycles, such as compound 1 (EC 50 = 575 nM), that showed the macrocycle was not required for activity. Structural information is particularly important when targeting PPIs, as without it, it can be difficult to tell where the ligand is binding to the protein and, therefore, to rationally make changes to improve the potency.…”

Modulation of IL-17 backbone dynamics reduces receptor affinity and reveals a new inhibitory mechanism

“…56 However, a number of small molecule inhibitors that target IL-17A have been reported. [16][17][18][19] Of these, perhaps the best studied have been based on the series of macrocycles patented by Ensemble, 23 which have been shown to bind in the central binding pocket. Previous crystallographic studies of IL-17:peptide:ligand complexes have suggested that these inhibitors of IL-17 function either by sterically blocking and/or inducing structural changes that preclude receptor binding.…”

“…Qualitative assessment of the binding isotherms of the IL-17AA and IL-17AF isoforms to IL-17RA suggest similar k on values, however notably the IL-17AA isoform shows no dissociation during the course of the experiment, whereas IL-17AF has a measurable k off . Previous studies 16,17,19 have suggested that small molecule inhibitors function by either causing structural changes that prevent receptor binding or by causing steric clashes. Our experiments, run in the presence of MC, suggests that IL-17AA binds both MC and IL-17RA simultaneously as only signicant effects on k off are observed resulting in approximately a 3-4-fold weaker K D .…”

“…15 The essence of therapeutic intervention strategies has been the inhibition of signalling complex formation through ligand binding to IL-17 dimers, which then prevents interaction with the receptors. Several studies have shown that small molecule inhibitors of IL17AA are able to bind in the central hydrophobic pocket, located between the two interior hairpins at the interface between the two halves of the homodimer [16][17][18][19] (see Fig. 1), while a recent study has identied a new binding site at the Cterminus.…”