Optimization of Selective and CNS Penetrant Alkyne-Based TREK Inhibitors: The Discovery and Characterization of ONO-9517601 (VU6022856) and ONO-7927846 (VU6024391)

  • J Med Chem. 2025 Nov 13;68(21):23554-23572. doi: 10.1021/acs.jmedchem.5c02535.
Motoyuki Tanaka  1 ,  Yoko Sekioka  2 ,  Gakuji Hashimoto  2 ,  Takahiro Mori  2 ,  Tomoyuki Shono  3 ,  Yuuki Isaji  4 ,  Katsuya Hisaichi  1 ,  Elizabeth S Childress  5  6 ,  Sean Bollinger  5  6 ,  Joza A Schmitt  5  6 ,  Trevor C Chopko  5  6 ,  Aaron T Garrison  5  6 ,  Charles K Perry  5  6 ,  Keagan Chronister  5  6 ,  Meghan Kramer  5  6 ,  Sichen Chang  5  6 ,  Katherine J Watson  5  6 ,  Jonathan W Dickerson  5  6 ,  Michael Bubser  5  6 ,  Jerri M Rook  5  6 ,  Carrie K Jones  5  6 ,  Olivier Boutaud  5  6 ,  Thomas M Bridges  5  6 ,  Jerod S Denton  5  6  7 ,  Darren W Engers  5  6 ,  Haruto Kurata  1 ,  Craig W Lindsley  5  6
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. Safety Research, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
  • 5. Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 6. Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
  • 7. Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.
PMID: 41104520 DOI: 10.1021/acs.jmedchem.5c02535
Abstract

Herein we describe the chemical optimization of a selective and CNS penetrant series of TREK inhibitors (the K2P family of potassium ion channels), culminating in the discovery of ONO-9517601 (VU6022856) and ONO-7927846 (VU6024391). Optimization of ONO-TR-772 focused on replacements for the N-Boc aniline moiety and identified N-acyl piperidine pyrazoles as attractive surrogates, affording excellent potency, PK profiles, CNS penetration and ion channel selectivity. ONO-9517601 and ONO-7927846 displayed robust efficacy in an MK-801 challenge rat NOR paradigm, with MEDs of 1 mg/kg and 0.3 mg/kg, respectively. These ligands represent valuable preclinical research tools for exploring selective TREK inhibition in vitro and in vivo.

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