Towards a TREK-1/2 (TWIK-Related K+ Channel 1 and 2) dual activator tool compound: Multi-dimensional optimization of BL-1249

Bioorg Med Chem Lett. 2019 Jul 1;29(13):1601-1604. doi: 10.1016/j.bmcl.2019.04.048. Epub 2019 Apr 29.

Abstract

This letter describes a focused, multi-dimensional optimization campaign around BL-1249, a fenamate class non-steroidal anti-inflammatory and a known activator of the K2P potassium channels TREK-1 (K2P2.1) and TREK-2 (K2P10.1). While BL-1249 has been widely profiled in vitro as a dual TREK-1/2 activator, poor physicochemical and DMPK properties have precluded a deeper understanding of the therapeutic potential of these key K2P channels across a broad spectrum of peripheral and central human disease. Here, we report multi-dimensional SAR that led to a novel TREK-1/2 dual activator chemotype, exemplified by ONO-2960632/VU6011992, with improved DMPK properties, representing a new lead for further optimization towards robust in vivo tool compounds.

Keywords: Activator; K(2P) channel; Potassium ion channel; TREK-1; TREK-2.

Publication types

  • Letter
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Potassium Channels, Tandem Pore Domain / metabolism*
  • Tetrahydronaphthalenes / pharmacology
  • Tetrahydronaphthalenes / therapeutic use*
  • Tetrazoles / pharmacology
  • Tetrazoles / therapeutic use*

Substances

  • (5,6,7,8-tetrahydronaphthalen-1-yl)-(2-(1H-tetrazol-5-yl)phenyl)amine
  • KCNK10 protein, human
  • Potassium Channels, Tandem Pore Domain
  • Tetrahydronaphthalenes
  • Tetrazoles
  • potassium channel protein TREK-1