从Eliapixant衍生的P2X3受体拮抗剂的开发，具有改善治疗慢性咳嗽的性能

IF 5.9 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2025-09-07 DOI:10.1016/j.ejmech.2025.118116

Yang Zang , Qun Li , Yang Li , Xiaohua Ding , Ruibin Liu , Lifei Liu , Hongna Sun , Lihan Qu , Xuejun Zhang

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引用次数: 0

摘要

P2X3受体是atp激活的离子通道，主要表达在外周感觉神经元上。其激活触发咳嗽反射通路，使其成为治疗慢性咳嗽的有吸引力的靶点，P2X3受体拮抗剂的发现一直是学术界和制药公司的长期追求。然而，初步的拮抗剂受到味觉障碍或药物性肝损伤的阻碍。我们在此描述的策略是在P2X3和P2X2/3受体之间保持适度的选择性，并用3-甲基丁烷-2-醇取代代谢不稳定的基序。这些发现的努力导致了HW091077的鉴定，这是一种P2X3受体拮抗剂，具有最佳的效力，选择性，PK和代谢特性平衡，已进入治疗慢性咳嗽的临床试验。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Development of a P2X3 receptor antagonist derived from eliapixant with improved properties for the treatment of chronic cough

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Development of a P2X3 receptor antagonist derived from eliapixant with improved properties for the treatment of chronic cough

The P2X3 receptor is an ATP-activated ion channel primarily expressed on peripheral sensory neurons. Its activation triggers cough reflex pathways, making it an attractive target for treating chronic cough and the discovery of P2X3 receptor antagonist has been a long-term pursuit by academia and pharmaceutical companies. However, preliminary antagonists have been hampered by taste disturbances or drug-induced liver injury. Our strategy described herein are maintaining a moderate selectivity between P2X3 and P2X2/3 receptors and replacing the metabolically labile motif with 3-methylbutan-2-ol. These discovery efforts lead to the identification of HW091077, a P2X3 receptor antagonist with an optimal balance of potency, selectivity, PK and metabolic properties that has advanced into clinical trials for the treatment of chronic cough.

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.