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

Yuzo Iwaki; Kentaro Yashiro; Masaya Kokubo; Takahiro Mori; Joshua M Wieting; Kevin M McGowan; Thomas M Bridges; Darren W Engers; Jerod S Denton; Haruto Kurata; Craig W Lindsley

doi:10.1016/j.bmcl.2019.04.048

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.

Authors

Affiliations

¹ Medicinal Chemistry Research Laboratories, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
² Discovery Research Laboratories, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
³ Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, TN 37232, USA.
⁴ Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, TN 37232, USA; Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
⁵ Medicinal Chemistry Research Laboratories, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan. Electronic address: [email protected].
⁶ Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA; Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: [email protected].

PMID: 31072652
DOI: 10.1016/j.bmcl.2019.04.048

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 K_2P potassium channels TREK-1 (K_2P2.1) and TREK-2 (K_2P10.1). 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 K_2P 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