Discovery of ONO-TR-772 (VU6018042): A Highly Selective and CNS Penetrant TREK Inhibitor in Vivo Tool Compound

Herein we describe our continuing work on the K₂P family of potassium ion channels with the chemical optimization of a selective and CNS penetrant series of TREK inhibitors, culminating in the discovery of ONO-TR-772 (VU6018042). From an HTS hit harboring a benzyl ether linker, SAR proved intractable until an acetylene linker was identified as an isosteric replacement. Robust SAR was then observed, and a key fluorination to enhance PK and CNS penetration provided ONO-TR-772 (VU6018042), a potent (TREK-1 IC₅₀ = 15 nM), selective (>10 μM versus other K₂P channels except TREK-2), and CNS penetrant (rat K _p = 0.98) TREK inhibitor. ONO-TR-772 (VU6018042) demonstrated robust efficacy in an MK-801 challenge NOR paradigm, with an MED of 10 mg/kg.