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

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

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.

Figures
Products