2. Academic Validation
  3. Piperazinotriazole-based NK3R antagonists: Rational design, synthesis, and identification of an orally active lead compound

Piperazinotriazole-based NK3R antagonists: Rational design, synthesis, and identification of an orally active lead compound

  • Eur J Med Chem. 2026 Mar 15:306:118614. doi: 10.1016/j.ejmech.2026.118614.
Fangxia Zou 1,  Yashi Zhou 1,  Hui Wang 2,  Hengwei Xu 1,  Wenjing Zhang 2,  Yifei Yang 3,  Chunmei Li 1,  Wenyan Wang 1,  Jianzhao Zhang 1,  Hongbo Wang 1,  Liang Ye 4,  Jingwei Tian 5
Affiliations

Affiliations

  • 1 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, PR China.
  • 2 State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai, Shandong, 264003, PR China.
  • 3 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, PR China; State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai, Shandong, 264003, PR China.
  • 4 School of Public Health and Management, Binzhou Medical University, Yantai, PR China. Electronic address: [email protected].
  • 5 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, PR China; State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai, Shandong, 264003, PR China. Electronic address: [email protected].
PMID: 41621224 DOI: 10.1016/j.ejmech.2026.118614
Abstract

The neurokinin-3 receptor (NK3R) has emerged as a promising non-hormonal therapeutic target for menopausal hot flashes, with fezolinetant being the only clinically approved NK3R Antagonist to date. To overcome this therapeutic limitation, we designed a series of imidazolepiperazine derivatives (17a-17c, 21, 23a-23u), among which 23i(R) demonstrated superior pharmacological properties including potent NK3R inhibition (IC50 = 65.42 ± 6.54 nM), strong target binding (IC50 = 53.61 ± 3.67 nM), excellent membrane permeability (Papp A-B = 27.3 × 10-6 cm/s; ER = 0.53), and remarkable oral bioavailability (165 %). In ovariectomized rat models, 23i(R) effectively suppressed luteinizing hormone levels while exhibiting favorable pharmacokinetics and tolerability, establishing it as a promising clinical candidate for further development as a next-generation NK3R Antagonist.

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