Discovery of Novel Small Molecule Dual Inhibitors Targeting Toll-Like Receptors <b>7</b> and <b>8</b>

Endosomal toll-like receptors (TLRs) <b>7</b> and <b>8</b> 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 (<b>1</b>) and a TLR8-specific inhibitor (<b>2</b>) based on our previous screen targeting TLR8. Compound <b>1</b>, bearing a benzanilide scaffold, was found to inhibit TLR7 and TLR8 at low micromolar concentrations. We envisioned making modifications on the benzanilide scaffold of <b>1</b> resulting in a class of highly specific TLR7 inhibitors. Our efforts led to the discovery of a new TLR8 inhibitor (<b>CU-115</b>) and identification of a TLR7/8 dual inhibitor (<b>CU-72</b>), 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 <b>2</b> and developed a new TLR8 inhibitor bearing a 1,3,4-oxadiazole motif.