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Войти в исследования Journal of medicinal chemistry · 2026
Structure-Based Design of Potent TLR7/8/9 Triple Antagonists: Overcoming High Tissue Distribution and Reactive Metabolite Liabilities.
СтатьяНазвание и аннотация: Перевод в очереди
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Zhang Zhiwei, Dey Fabian, Liu Haixia, Rudolph Markus G, Liu Yafei, Wang Xiaoqing, Zhang Weixing, Zhang Zhisen, Kou Buyu, Zou Ge, Hu Taishan, Schlatter Daniel, Ehler Andreas, Benz Jörg, Sokoll Kristin, Kaiser Tina, Gsell Bernard, Ding Haiyuan, Lin Zhaohu, Zhu Lina, Dai Lue, Shen Fang, Wu Jianquan, Yu Xin, Dai Jieyu, Qiu Hongxia, Jiang Tianyi, Lassen Kara G, Shen Hong C, Zhu Wei
Аннотация
Sustained activation of endosomal Toll-like receptors (TLR) 7, 8, and 9 by self-nucleic acids is considered to be a key driver for autoimmune diseases, e.g., systemic lupus erythematosus (SLE). We report the discovery of a novel series of potent, orally bioavailable TLR7/8/9 triple antagonists featuring a unique "N-aryl-N" pharmacophore. Guided by TLR8 cocrystal structures and TLR7/9 homology models, we systematically optimized the series to balance pan-TLR potency with drug-like properties. Strategic modulation of lipophilicity and basicity successfully reduced the high volume of distribution (Vss) observed in mouse for early leads. Further compound optimization eliminated a reactive metabolite (GSH) liability. The resulting lead, compound 41, demonstrated robust dose-dependent inhibition of TLR7 and TLR9 pathways in mouse challenging models, supporting the potential of a TLR7/8/9 triple antagonist for treating autoimmune diseases.