KBD-4466

The Toll-like receptor (TLR) family comprises a class of proteins that play a critical role in the innate immune system. Toll-like receptors TLR7 and TLR8 are transmembrane receptors that recognize single-stranded RNA. Aberrant activation of TLR7/8 is associated with the progression of certain autoimmune diseases, such as lupus. Therefore, highly selective inhibitors of TLR7/8 would be an effective therapeutic approach. Here, we have discovered a small molecule inhibitor, KBD4466 (19), which demonstrates excellent cellular activity, favorable pharmacokinetic properties, potent inhibition of cytokine production in mouse pharmacodynamic studies, and outstanding therapeutic efficacy in an SLE animal model. Furthermore, we have developed an efficient synthetic route to access a [3.1.0] bicyclic system featuring chiral contiguous quaternary carbon centers.