Further hit optimization of 6-(trifluoromethyl)pyrimidin-2-amine based TLR8 modulators: Synthesis, biological evaluation and structureeactivity relationships

Toll-like receptor 8 (TLR8) is an endosomal TLR that has an important role in the innate human immune system, which is involved in numerous pathological conditions. Excessive activation of TLR8 can lead to inflammatory and autoimmune diseases, which highlights the need for development of TLR8 modulators. However, only a few small-molecule modulators that selectively target TLR8 have been developed. Here, we report the synthesis and systematic investigation of the structureeactivity relationships of a series of novel TLR8 negative modulators based on previously reported 6-(trifluoromethyl)pyrimidin-2-amine derivatives. Four compounds showed low-micromolar concentration-dependent inhibition of TLR8-mediated signaling in HEK293 cells. These data confirm that the 6-trifluoromethyl group and two other substituents on positions 2 and 4 are important structural elements of pyrimidine-based TLR8 modulators. Substitution of the main scaffold at position 2 with a methylsulfonyl group or para hydroxy/hydroxymethyl substituted benzylamine is essential for potent negative modulation of TLR8. Our best-inclass TLR8-selective modulator 53 with IC50 value of 6.2 mu M represents a promising small-molecule chemical probe for further optimization to a lead compound with potent immunomodulatory properties. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

TLR8, an endosomal Toll-like receptor in human innate immune system, plays a crucial role in inflammation and autoimmune diseases. Novel negative modulators based on pyrimidine structure show potential as immunomodulatory agents for further development towards lead compounds with potent immunomodulatory properties.