2. Academic Validation
  3. Discovery of ONO-2920632 (VU6011887): A Highly Selective and CNS Penetrant TREK-2 (TWIK-Related K+ Channel 2) Preferring Activator In Vivo Tool Compound

Discovery of ONO-2920632 (VU6011887): A Highly Selective and CNS Penetrant TREK-2 (TWIK-Related K+ Channel 2) Preferring Activator In Vivo Tool Compound

  • ACS Chem Neurosci. 2025 Mar 5;16(5):960-967. doi: 10.1021/acschemneuro.5c00032.
Kentaro Yashiro 1,  Yuzo Iwaki 1,  Hirohito Urata 1,  Masaya Kokubo 1,  Takahiro Mori 2,  Yoko Sekioka 2,  Koichi Isami 2,  Junya Kato 3,  Joshua Wieting 4 5,  Kevin M McGowan 4 5,  Thomas M Bridges 4 5,  Olivier Boutaud 4 5,  Darren W Engers 4 5,  Jerod S Denton 6,  Haruto Kurata 1,  Craig W Lindsley 4 5 7 8
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 Pharmacokinetic Research, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
  • 4 Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 5 Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
  • 6 Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.
  • 7 Department of Chemistry, Vanderbilt University, Nashville Tennessee 37232, United States.
  • 8 Department of Biochemistry, Vanderbilt University, Nashville Tennessee 37232, United States.
PMID: 39981749 DOI: 10.1021/acschemneuro.5c00032
Abstract

Herein we describe our initial work on the K2P family of potassium ion channels with the chemical optimization and characterization of a novel series of TWIK-Related K+ Channel (TREK)-1/2 dual activators and TREK-2 preferring activators derived from a high-throughput screening hit. The exercise provided TREK activators with good CNS penetration and Others with low CNS exposure to enable exploration of both central and peripheral TREK activation. From this, ONO-2920632 (VU6011887 = 19b) emerged as a reasonably potent (human Tl+; TREK-1 EC50 = 2.8 μM (95% Emax), TREK-2 EC50 = 0.30 μM (184% Emax)), first-generation CNS penetrant (rat Kp = 0.37) in vivo tool compound with selectivity versus the Other K2P channels (>91-fold selective vs TASK1, TASK2, TASK3, TRAAK, TWIK2, and 31-fold selective vs TRESK) and no significant activity in a large ancillary pharmacology panel. ONO-2920632 (VU6011887) displayed robust, dose dependent efficacy when dosed orally in a mouse pain model (acetic acid writhing assay), where it was equipotent at 3 mg/kg to the assay standard indomethacin at 10 mg/kg. The therapeutic potential of TREK channel activation has long been hampered by a lack of selective, small molecule tools, and this work provides a variety of in vivo tool compounds for the community.

Keywords

K2P (two-pore domain potassium channel); TREK (TWIK-Related K+ Channel); ion channel; pain.

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