Discovery of ONO-TR-772 (VU6018042): A Highly Selective and CNS Penetrant TREK Inhibitor in Vivo Tool Compound

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-04-28 DOI:10.1021/acsmedchemlett.5c0021510.1021/acsmedchemlett.5c00215

Motoyuki Tanaka, Takahiro Mori, Gakuji Hashimoto, Katsukuni Mitsui, Akihiro Kishi, Elizabeth S. Childress, Sean R. Bollinger, Trevor C. Chopko, Thomas M. Bridges, Douglas G. Stafford, Zhonping Huang, Mark A. Wolf, Darren W. Engers, Jerod S. Denton, Haruto Kurata* and Craig W. Lindsley*,

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Abstract

Herein we describe our continuing work on the K₂P family of potassium ion channels with the chemical optimization of a selective and CNS penetrant series of TREK inhibitors, culminating in the discovery of ONO-TR-772 (VU6018042). From an HTS hit harboring a benzyl ether linker, SAR proved intractable until an acetylene linker was identified as an isosteric replacement. Robust SAR was then observed, and a key fluorination to enhance PK and CNS penetration provided ONO-TR-772 (VU6018042), a potent (TREK-1 IC₅₀ = 15 nM), selective (>10 μM versus other K₂P channels except TREK-2), and CNS penetrant (rat K_p = 0.98) TREK inhibitor. ONO-TR-772 (VU6018042) demonstrated robust efficacy in an MK-801 challenge NOR paradigm, with an MED of 10 mg/kg.

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ONO-TR-772 (VU6018042)：一种高选择性和中枢神经系统渗透的TREK抑制剂体内工具化合物的发现

在这里，我们描述了我们对K2P家族钾离子通道的持续研究，并对选择性和CNS渗透的TREK抑制剂系列进行了化学优化，最终发现了ONO-TR-772 （VU6018042）。从含有苯醚连接剂的HTS命中，SAR被证明是难以处理的，直到乙炔连接剂被确定为等构替代物。结果表明，ONO-TR-772 （VU6018042）是一种强效（TREK-1 IC50 = 15 nM）、选择性（与TREK-2以外的其他K2P通道相比= 10 μM）和CNS渗透（大鼠Kp = 0.98）的TREK抑制剂，可以增强PK和CNS穿透。ONO-TR-772 （VU6018042）在MK-801挑战性NOR范式中显示出强大的疗效，MED为10 mg/kg。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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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.