Discovery ofONO-2920632 (VU6011887): A Highly Selectiveand CNS Penetrant TREK‑2 (TWIK-Related K+ Channel 2) PreferringActivator <i>In Vivo</i> Tool Compound

Herein we describe our initial work on the K₂P family of potassium ion channels with the chemical optimization and characterization of a novel series of TWIK-Related K+ Channel (TREK)-1/2 dual activators and TREK-2 preferring activators derived from a high-throughput screening hit. The exercise provided TREK activators with good CNS penetration and others with low CNS exposure to enable exploration of both central and peripheral TREK activation. From this, ONO-2920632 (VU6011887 = <b>19b</b>) emerged as a reasonably potent (human Tl⁺; TREK-1 EC₅₀ = 2.8 μM (95% <i>E</i>_max), TREK-2 EC₅₀ = 0.30 μM (184% <i>E</i>_max)), first-generation CNS penetrant (rat K_p = 0.37) <i>in vivo</i> tool compound with selectivity versus the other K₂P channels (>91-fold selective vs TASK1, TASK2, TASK3, TRAAK, TWIK2, and 31-fold selective vs TRESK) and no significant activity in a large ancillary pharmacology panel. ONO-2920632 (VU6011887) displayed robust, dose dependent efficacy when dosed orally in a mouse pain model (acetic acid writhing assay), where it was equipotent at 3 mg/kg to the assay standard indomethacin at 10 mg/kg. The therapeutic potential of TREK channel activation has long been hampered by a lack of selective, small molecule tools, and this work provides a variety of <i>in vivo</i> tool compounds for the community.