Discovery of Potent and Selective Quinoline-Based Toll-like Receptor 9 Antagonists

The Toll-like receptor (TLR) family are critical components of the innate immune system, acting as pattern recognition receptors that detect microbial components and initiate immune responses. In humans, 10 TLRs have been identified, each recognizing distinct pathogen-associated molecular patterns. Among these, TLR9 is unique in its ability to sense CpG motifs, playing a crucial role in the detection of bacterial and viral DNA. Despite its significance, targeting TLR9 for therapeutics has proven to be challenging. Herein we describe the discovery of a series of potent and selective TLR9 antagonists, represented by 5-(hexahydropyrrolo-[3,4-<i>b</i>]-pyrrol-1-(2<i>H</i>)-yl)-quinoline (<b>38</b>), with an IC₅₀ value of 0.1 nM against hTLR9 and >10,000-fold selectivity over hTLR2/4/5/7/8. Compound <b>38</b> demonstrated good pharmacokinetic and excellent pharmacodynamic features, indicating its potential utility as a pharmacological tool and a therapeutic candidate for TLR9 related disorders.