Optimization of Selective and CNS Penetrant Alkyne-Based TREK Inhibitors: The Discovery and Characterization of ONO-9517601 (VU6022856) and ONO-7927846 (VU6024391)
Herein we describe the chemical optimization of a selective and CNS penetrant series of TREK inhibitors (the K<sub>2</sub>P 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 <i>N</i>-Boc aniline moiety and identified <i>N</i>-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 <i>in vitro</i> and <i>in vivo</i>.
Authors
- Thomas M. Bridges (ORCID: https://orcid.org/0000-0002-0491-4796)
- Jonathan W. Dickerson (ORCID: https://orcid.org/0000-0001-7263-3788)
- Gakuji Hashimoto
- Michael Bubser (ORCID: https://orcid.org/0000-0002-0583-5248)
- Keagan S. Chronister
- Takahiro Mori (ORCID: https://orcid.org/0000-0002-2754-5858)
- Katherine J. Watson
- Elizabeth S. Childress
- Darren W. Engers (ORCID: https://orcid.org/0000-0002-3633-3072)
- Trevor C. Chopko (ORCID: https://orcid.org/0009-0005-1036-3635)
- Sean R. Bollinger
- Joza Schmitt (ORCID: https://orcid.org/0000-0001-9244-4909)
- H. Kurata (ORCID: https://orcid.org/0000-0002-9009-3428)
- Jerod S. Denton (ORCID: https://orcid.org/0000-0003-0032-8586)
- Tomoyuki Shono
- Yoko Sekioka
- Carrie K. Jones (ORCID: https://orcid.org/0000-0002-1287-9839)
- Aaron T. Garrison (ORCID: https://orcid.org/0000-0003-4779-1922)
- Craig W. Lindsley (ORCID: https://orcid.org/0000-0003-0168-1445)
- Jerri M. Rook (ORCID: https://orcid.org/0000-0003-4029-0148)
- Meghan Kramer
- Katsuya Hisaichi
- Olivier G. Boutaud (ORCID: https://orcid.org/0000-0002-8910-0598)
- Charles K. Perry (ORCID: https://orcid.org/0000-0001-9835-3434)
- Motoyuki Tanaka
- Sichen Chang
- Yuuki Isaji
Institutions
- Vanderbilt University (US)
- Ono Pharmaceutical (Japan) (JP)
- Center for Discovery (US)
- Vanderbilt University Medical Center (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-10-17
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c02535
- Primary Topic
- Neuroscience and Neuropharmacology Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00