Identification of a Human Toll-Like Receptor (TLR) 8‑Specific Agonist and a Functional Pan-TLR Inhibitor in 2‑Aminoimidazoles

Activation
of human toll-like receptor-8 (TLR8), expressed in myeloid
dendritic cells, monocytes, and monocyte-derived dendritic cells,
evokes a distinct cytokine profile which favors the development of
Type 1 helper T cells. Part-structures of the 2-aminobenzimidazole
scaffold were examined with a view to identifying structural requisites
corresponding to the smallest possible fragment of the benzimidazole
core that would allow for retention of TLR8-agonistic activity. TLR8-specific
agonistic activity was retained in 1-pentyl-4-phenyl-1H-imidazol-2-amine. The crystal structure of this compound bound to
the TLR8 ectodomain displayed binding interactions that are common
to other TLR8 agonists. This compound showed markedly attenuated proinflammatory
properties in ex vivo human blood models. SAR studies
revealed that 4-(2-(benzyloxy)­phenyl)-1-pentyl-1H-imidazol-2-amine inhibited TLR signaling in a variety of TLR reporter
cell lines, as well as in pharmacologically relevant human blood model
systems. A kinase screen of this compound showed relative specificity
for calmodulin kinases.