咪唑吡啶
化学
体内
TLR9型
TLR7型
生物化学
药理学
受体
立体化学
生物
先天免疫系统
Toll样受体
基因表达
生物技术
基因
DNA甲基化
作者
Nirmal K. Das,Purbita Bandopadhyay,Supriya Roy,Bishnu Prasad Sinha,Uddipta Ghosh Dastidar,Oindrila Rahaman,Sourav Pal,Dipyaman Ganguly,Arindam Talukdar
标识
DOI:10.1021/acs.jmedchem.2c00386
摘要
Undesirable activation of endosomal toll-like receptors TLR7 and TLR9 present in specific immune cells in response to host-derived ligands is implicated in several autoimmune diseases and other contexts of autoreactive inflammation, making them important therapeutic targets. We report a drug development strategy identifying a new chemotype for incorporating relevant structural subunits into the basic imidazopyridine core deemed necessary for potent TLR7 and TLR9 dual antagonism. We established minimal pharmacophoric features in the core followed by hit-to-lead optimization, guided by in vitro and in vivo biological assays and ADME. A ligand-receptor binding hypothesis was proposed, and selectivity studies against TLR8 were performed. Oral absorption and efficacy of lead candidate 42 were established through favorable in vitro pharmacokinetics and in vivo pharmacodynamic studies, with IC50 values of 0.04 and 0.47 μM against TLR9 and TLR7, respectively. The study establishes imidazopyridine as a viable chemotype to therapeutically target TLR9 and TLR7 in relevant clinical contexts.
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