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

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-08-26 DOI:10.1021/acsmedchemlett.5c00248

Xue Song, Chen-Guo Feng, Chen Wang, Jay Cheng* and Guo-Qiang Lin*,

引用次数: 0

Abstract

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-b]pyrrol-1(2H)-yl)quinoline (38), with an IC₅₀ value of 0.1 nM against hTLR9 and >10,000-fold selectivity over hTLR2/4/5/7/8. Compound 38 demonstrated good pharmacokinetic and excellent pharmacodynamic features, indicating its potential utility as a pharmacological tool and a therapeutic candidate for TLR9 related disorders.

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强效选择性喹啉类toll样受体9拮抗剂的发现

toll样受体（TLR）家族是先天免疫系统的重要组成部分，作为模式识别受体，检测微生物成分并启动免疫反应。在人类中，已鉴定出10个tlr，每个tlr识别不同的病原体相关分子模式。其中，TLR9具有独特的感知CpG基序的能力，在检测细菌和病毒DNA中起着至关重要的作用。尽管具有重要意义，但以TLR9为靶点进行治疗已被证明具有挑战性。在此，我们描述了一系列有效的选择性TLR9拮抗剂的发现，以5-（六氢吡咯[3,4-b]吡咯-1(2H)-基）喹啉为代表（38），其对hTLR9的IC50值为0.1 nM，选择性为hTLR2/4/5/7/8的10000倍。化合物38表现出良好的药代动力学和良好的药效学特征，表明其作为TLR9相关疾病的药理工具和治疗候选药物的潜在效用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.