高效神经激肽- 3受体抑制剂的开发：设计、合成和评价。

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-06-26 eCollection Date: 2025-07-10 DOI:10.1021/acsmedchemlett.5c00230

Shengmin Ji, Hui Wang, Hengwei Xu, Wenjing Zhang, Yifei Yang, Chunmei Li, Wenyan Wang, Liang Ye, Jianzhao Zhang, Hongbo Wang, Jingwei Tian, Fangxia Zou

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引用次数: 0

摘要

神经激肽-3受体（NK3R）已成为一个有前景的治疗靶点。最近的证据表明，口服NK3R拮抗剂阻断神经激肽B信号传导可显著缓解潮热症状。尽管有这种潜力，迄今为止只有一种NK3R配体（ESN-364）被临床批准。为了弥补这一空白，我们通过合理的设计和合成，开发了一系列咪唑-哌嗪衍生物（13a-13l， 17a-17f和22a-22i）。分子对接验证了结构原理，化合物22i显示出优越的靶标结合能力和强大的NK3R抑制活性。值得注意的是，22i具有增强的膜通透性和高口服生物利用度。体内疗效研究显示，口服22i有效抑制黄体生成素水平，支持其进一步优化的潜力。

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Development of a Highly Potent Neurokinin‑3 Receptor Inhibitor: Design, Synthesis, and Evaluation.

The neurokinin-3 receptor (NK3R) has emerged as a promising therapeutic target. Recent evidence indicates that oral administration of an NK3R antagonist to block neurokinin B signaling significantly alleviates hot flash symptoms. Despite this potential, only one NK3R ligand (ESN-364) has been clinically approved to date. To address this gap, we developed a series of imidazole-piperazine derivatives (13a-13l, 17a-17f, and 22a-22i) through rational design and synthesis. Molecular docking validated the structural rationale, with compound 22i demonstrating superior target binding potency and robust NK3R inhibitory activity. Notably, 22i exhibited an enhanced membrane permeability and high oral bioavailability. In vivo efficacy studies revealed that oral 22i effectively suppressed luteinizing hormone levels, supporting its potential for further optimization.

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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.