Discovery of Novel Small Molecule Dual Inhibitors Targeting Toll-Like Receptors 7 and 8

Endosomal toll-like receptors (TLRs) 7 and 8 recognize viral single-stranded RNAs, a class of imidazoquinoline
compounds, 8-oxo-adenosines, 8-aminobenzodiazepines, pyrimidines,
and guanosine analogues. Substantial evidence is present linking chronic
inflammation mediated specifically by TLR7 to the progression of autoimmunity.
We identified a new TLR7/8 dual inhibitor (1) and a TLR8-specific
inhibitor (2) based on our previous screen targeting
TLR8. Compound 1, bearing a benzanilide scaffold, was
found to inhibit TLR7 and TLR8 at low micromolar concentrations. We
envisioned making modifications on the benzanilide scaffold of 1 resulting in a class of highly specific TLR7 inhibitors.
Our efforts led to the discovery of a new TLR8 inhibitor (CU-115) and identification of a TLR7/8 dual inhibitor (CU-72), bearing a distinct diphenyl ether skeleton, with potential for
TLR7 selectivity optimization. Given the role of TLR8 in autoimmunity,
we also optimized the potency of 2 and developed a new
TLR8 inhibitor bearing a 1,3,4-oxadiazole motif.

内吞体Toll样受体7和8识别病毒单链RNA、咪唑喹啉类化合物、8-氧代腺苷、8-氨基苯并二氮杂卓、嘧啶和鸟苷类似物。大量证据表明，由TLR7介导的慢性炎症与自身免疫的进展密切相关。基于我们对TLR8的先前筛选，我们鉴定了一种新的TLR7/8双抑制剂（1）和一种TLR8特异性抑制剂（2）。化合物1，含苯并甲酰脲骨架，在低微摩尔浓度下被发现可抑制TLR7和TLR8。我们设想对化合物1的苯并甲酰脲骨架进行修饰，以产生一类高特异性的TLR7抑制剂。我们的努力导致了新型TLR8抑制剂（CU-115）的发现以及TLR7/8双抑制剂（CU-72）的鉴定，该抑制剂具有独特的二苯基醚骨架，并具有优化TLR7选择性的潜力。鉴于TLR8在自身免疫中的作用，我们还优化了化合物2的效力，并开发了一种带有1,3,4-恶二唑基序的新TLR8抑制剂。