# Optimization of Selective and CNS Penetrant Alkyne-Based TREK Inhibitors: The Discovery and Characterization of ONO-9517601 (VU6022856) and ONO-7927846 (VU6024391)

## TL;DR

This paper describes the development of two potent and brain-penetrant inhibitors of TREK potassium channels for potential use in preclinical research.

## Contribution

The discovery of ONO-9517601 and ONO-7927846 as selective TREK inhibitors with strong CNS penetration and efficacy.

## Key findings

- N-acyl piperidine pyrazoles improved potency, PK profiles, and CNS penetration in TREK inhibitors.
- ONO-9517601 and ONO-7927846 showed robust efficacy in an MK-801 challenge rat NOR paradigm.
- The compounds represent valuable tools for studying selective TREK inhibition in vitro and in vivo.

## 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.