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
  • 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 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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