2. Academic Validation
  3. Synthesis and evaluation of piperazinotriazoles. Discovery of a potent and orally bioavailable neurokinin-3 receptor inhibitor

Synthesis and evaluation of piperazinotriazoles. Discovery of a potent and orally bioavailable neurokinin-3 receptor inhibitor

  • Eur J Med Chem. 2023 Sep 5;257:115486. doi: 10.1016/j.ejmech.2023.115486.
Liang Ye 1,  Yifei Yang 2,  Chunmei Li 2,  Jianzhao Zhang 3,  Wenyan Wang 2,  Mingxu Ma 2,  Hengwei Xu 4,  Wenjing Zhang 4,  Fangxia Zou 2,  Zhengping Hu 5,  Hongbo Wang 6,  Jingwei Tian 7
Affiliations

Affiliations

  • 1 School of Public Health and Management, Binzhou Medical University, Yantai, PR China. Electronic address: [email protected].
  • 2 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.
  • 3 College of Life Sciences, Yantai University, Yantai, Shangdong, 264005, PR China.
  • 4 R & D Center, Luye Pharma Group Ltd., Yantai, 264003, PR China.
  • 5 Medicine & Pharmacy Research Center, Binzhou Medical University, Yantai, PR China.
  • 6 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. Electronic address: [email protected].
  • 7 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. Electronic address: [email protected].
PMID: 37247507 DOI: 10.1016/j.ejmech.2023.115486
Abstract

The neurokinin-3 receptor (NK3R) is one of three receptors that recognize neurokinins. The finding that pharmacological blockade of neurokinin B (NKB) signaling with an oral NK3R antagonist can significantly improve hot flash symptoms independent of any hormonal effect fits strongly suggest that NK3R is a viable drug target and that drugs targeting this receptor could be novel pharmacotherapies. Currently no NK3R ligands have been approved for the treatment of human disorders. Herein, we designed and synthesized a series of novel imidazolepiperazine derivatives (16a-16x, 20a-20f, 29a-29m) and performed molecular docking to confirm the design, among which the target compound 16x exhibited promising inhibitory activity against NK3R (IC50 = 430.60 nM) with excellent membrane permeability (Papp, A-B = 37.6 × 10-6 cm/s, ER < 1) and oral bioavailability (F% = 93.6%). Our in vivo studies demonstrated that 16x was orally active, efficacious, and well-tolerated in ovariectomy (OVX) model to suppress blood luteinizing hormone levels, which suggests that 16x is a viable lead compound for further optimization and development.

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