{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["68(21)"],"submitter":["Tanaka M"],"pubmed_abstract":["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>."],"journal":["Journal of medicinal chemistry"],"pagination":["23554-23572"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12621189"],"repository":["biostudies-literature"],"pubmed_title":["Optimization of Selective and CNS Penetrant Alkyne-Based TREK Inhibitors: The Discovery and Characterization of ONO-9517601 (VU6022856) and ONO-7927846 (VU6024391)."],"pmcid":["PMC12621189"],"pubmed_authors":["Watson KJ","Kurata H","Garrison AT","Schmitt JA","Denton JS","Sekioka Y","Lindsley CW","Bridges TM","Hisaichi K","Mori T","Bubser M","Childress ES","Tanaka M","Bollinger S","Hashimoto G","Shono T","Engers DW","Isaji Y","Chopko TC","Chang S","Boutaud O","Chronister K","Dickerson JW","Jones CK","Kramer M","Rook JM","Perry CK"],"additional_accession":[]},"is_claimable":false,"name":"Optimization of Selective and CNS Penetrant Alkyne-Based TREK Inhibitors: The Discovery and Characterization of ONO-9517601 (VU6022856) and ONO-7927846 (VU6024391).","description":"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>.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Nov","modification":"2026-06-05T15:21:13.083Z","creation":"2026-06-05T03:06:43.527Z"},"accession":"S-EPMC12621189","cross_references":{"pubmed":["41104520"],"doi":["10.1021/acs.jmedchem.5c02535"]}}