2. Academic Validation
  3. An anthrone-based Kv7.2/7.3 channel blocker with improved properties for the investigation of psychiatric and neurodegenerative disorders

An anthrone-based Kv7.2/7.3 channel blocker with improved properties for the investigation of psychiatric and neurodegenerative disorders

  • Bioorg Med Chem Lett. 2019 Dec 1;29(23):126681. doi: 10.1016/j.bmcl.2019.126681.
Jacob D Porter 1,  Oscar Vivas 2,  C David Weaver 3,  Abdulmohsen Alsafran 1,  Elliot DiMilo 4,  Leggy A Arnold 4,  Eamonn J Dickson 2,  Chris Dockendorff 5
Affiliations

Affiliations

  • 1 Department of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, WI 53201-1881, USA.
  • 2 Department of Physiology & Membrane Biology, University of California, 1 Shields Avenue, Davis, CA 95616, USA.
  • 3 Departments of Pharmacology and Chemistry, Vanderbilt University, Vanderbilt Institute of Chemical Biology, Nashville, TN 37232, USA.
  • 4 Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin, Milwaukee, WI 53211, USA.
  • 5 Department of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, WI 53201-1881, USA. Electronic address: christopher.dockendorff@mu.edu.
PMID: 31668424 DOI: 10.1016/j.bmcl.2019.126681
Abstract

A set of novel Kv7.2/7.3 (KCNQ2/3) channel blockers was synthesized to address several liabilities of the known compounds XE991 (metabolic instability and CYP inhibition) and the clinical compound DMP 543 (acid instability, insolubility, and lipophilicity). Using the anthrone scaffold of the prior channel blockers, alternative heteroarylmethyl substituents were installed via enolate alkylation reactions. Incorporation of a pyridazine and a fluorinated pyridine gave an analog (compound 18, JDP-107) with a promising combination of potency (IC50 = 0.16 μM in a Kv7.2 thallium flux assay), efficacy in a Kv7.2/7.3 patch clamp assay, and drug-like properties.

Keywords

DMP 543; JDP-107; Kv7 blocker; Schizophrenia; Voltage-gated potassium channel.

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