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

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.
Yuzo Iwaki 1,  Kentaro Yashiro 1,  Masaya Kokubo 1,  Takahiro Mori 2,  Joshua M Wieting 3,  Kevin M McGowan 3,  Thomas M Bridges 3,  Darren W Engers 3,  Jerod S Denton 4,  Haruto Kurata 5,  Craig W Lindsley 6
Affiliations

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: h.kurata@ono.co.jp.
  • 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: craig.lindsley@vanderbilt.edu.
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 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.

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