ONO-TR-772（VU6018042）的发现：一种高选择性且可穿透中枢神经系统的TREK抑制剂工具化合物。
Discovery of ONO-TR-772 (VU6018042): A Highly Selective and CNS Penetrant TREK Inhibitor Tool Compound.
作者信息
Tanaka Motoyuki, Mori Takahiro, Hashimoto Gakuji, Mitsui Katsukuni, Kishi Akihiro, Childress Elizabeth S, Bollinger Sean R, Chopko Trevor C, Bridges Thomas M, Stafford Douglas G, Huang Zhonping, Wolf Mark A, Engers Darren W, Denton Jerod S, Kurata Haruto, Lindsley Craig W
机构信息
Drug Discovery Chemistry, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
Research Center of Neurology, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
出版信息
ACS Med Chem Lett. 2025 Apr 28;16(5):896-901. doi: 10.1021/acsmedchemlett.5c00215. eCollection 2025 May 8.
Herein we describe our continuing work on the KP 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 IC = 15 nM), selective (>10 μM versus other KP channels except TREK-2), and CNS penetrant (rat = 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.
在此，我们描述了我们在钾离子通道KP家族方面的持续工作，即对一系列具有选择性且能穿透中枢神经系统的TREK抑制剂进行化学优化，最终发现了ONO-TR-772（VU6018042）。从一个带有苄基醚连接子的高通量筛选命中化合物开始，直到确定乙炔连接子作为等排体替代物之前，构效关系研究一直难以进行。随后观察到了稳定的构效关系，并且通过关键的氟化作用来增强药代动力学性质和中枢神经系统渗透性，从而得到了ONO-TR-772（VU6018042），一种强效的（TREK-1 IC = 15 nM）、选择性的（相对于除TREK-2之外的其他KP通道大于10 μM）且能穿透中枢神经系统的（大鼠 = 0.98）TREK抑制剂。ONO-TR-772（VU6018042）在MK-801激发的新物体识别范式中显示出强大的效力，半数有效剂量为10 mg/kg。
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