2. Academic Validation
  3. Development of a P2X3 receptor antagonist derived from eliapixant with improved properties for the treatment of chronic cough

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

  • Eur J Med Chem. 2025 Dec 15:300:118116. doi: 10.1016/j.ejmech.2025.118116.
Yang Zang 1,  Qun Li 1,  Yang Li 1,  Xiaohua Ding 1,  Ruibin Liu 1,  Lifei Liu 1,  Hongna Sun 1,  Lihan Qu 1,  Xuejun Zhang 2
Affiliations

Affiliations

  • 1 Hubei Bio-Pharmaceutical Industrial Technological Institute Inc., No. 666 High Tech Avenue, East Lake High Tech Development Zone, Wuhan, Hubei, 430075, China; Humanwell Healthcare (Group) Co., Ltd., No. 666 High Tech Avenue, East Lake High Tech Development Zone, Wuhan, Hubei, 430075, China.
  • 2 Hubei Bio-Pharmaceutical Industrial Technological Institute Inc., No. 666 High Tech Avenue, East Lake High Tech Development Zone, Wuhan, Hubei, 430075, China; Humanwell Healthcare (Group) Co., Ltd., No. 666 High Tech Avenue, East Lake High Tech Development Zone, Wuhan, Hubei, 430075, China. Electronic address: zhangxuejun@renfu.com.cn.
PMID: 40946532 DOI: 10.1016/j.ejmech.2025.118116
Abstract

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.

Keywords

ATP-Gated ion channel receptor; Antagonist; Chronic cough; P2X3.

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