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

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

  • ACS Med Chem Lett. 2025 Apr 28;16(5):896-901. doi: 10.1021/acsmedchemlett.5c00215.
Motoyuki Tanaka 1,  Takahiro Mori 2,  Gakuji Hashimoto 2,  Katsukuni Mitsui 2,  Akihiro Kishi 2,  Elizabeth S Childress 3 4,  Sean R Bollinger 3 4,  Trevor C Chopko 3 4,  Thomas M Bridges 3 4,  Douglas G Stafford 5,  Zhonping Huang 5,  Mark A Wolf 5,  Darren W Engers 3 4,  Jerod S Denton 3 4 6,  Haruto Kurata 1,  Craig W Lindsley 3 4
Affiliations

Affiliations

  • 1 Drug Discovery Chemistry, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
  • 2 Research Center of Neurology, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
  • 3 Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 4 Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
  • 5 Curia Global, Inc., 24 Corporate Circle, Albany, New York 12203, United States.
  • 6 Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.
PMID: 40365404 DOI: 10.1021/acsmedchemlett.5c00215
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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