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

Jacob D. Porter, Oscar Vivas, C. David Weaver, Abdulmohsen Alsafran, Elliot DiMilo, Leggy A. Arnold, Eamonn J. Dickson, Chris Dockendorff

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number126681
JournalBioorganic and Medicinal Chemistry Letters
Volume29
Issue number23
DOIs
StatePublished - Dec 1 2019

Fingerprint

Thallium
Alkylation
Neurodegenerative Diseases
Inhibitory Concentration 50
Psychiatry
Assays
Acids
Clamping devices
Scaffolds
Pharmaceutical Preparations
Solubility
Fluxes
pyridine
pyridazine
DMP 543
compound 18
anthrone

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

An anthrone-based Kv7.2/7.3 channel blocker with improved properties for the investigation of psychiatric and neurodegenerative disorders. / Porter, Jacob D.; Vivas, Oscar; Weaver, C. David; Alsafran, Abdulmohsen; DiMilo, Elliot; Arnold, Leggy A.; Dickson, Eamonn J.; Dockendorff, Chris.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 29, No. 23, 126681, 01.12.2019.

Research output: Contribution to journalArticle

Porter, Jacob D. ; Vivas, Oscar ; Weaver, C. David ; Alsafran, Abdulmohsen ; DiMilo, Elliot ; Arnold, Leggy A. ; Dickson, Eamonn J. ; Dockendorff, Chris. / An anthrone-based Kv7.2/7.3 channel blocker with improved properties for the investigation of psychiatric and neurodegenerative disorders. In: Bioorganic and Medicinal Chemistry Letters. 2019 ; Vol. 29, No. 23.
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