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

Abstract

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 Kp = 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.