2025/10/17 by Motoyuki Tanaka, Yoko Sekioka, Gakuji Hashimoto +28
Biochemistry, Genetics and Molecular Biology · Neuroscience · #Drug discovery #Ion channel #Ion channel regulation and function #Moiety #Neuroscience and Neuropharmacology Research #Penetrant (biochemical) #Pharmacological Receptor Mechanisms and Effects #Piperidine #Potassium channel
paper · pdf · doi:10.1021/acs.jmedchem.5c02535
published in Journal of Medicinal Chemistry 68(21), 23554-23572 (American Chemical Society)
openalex publication_date 2025/10/17 · openalex created_date 2025/10/18 · openalex updated_date 2026/08/01
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.