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

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.

• Authors: Jacob D Porter, Oscar Vivas, C David Weaver, Abdulmohsen Alsafran, Elliot DiMilo, Leggy A Arnold, Eamonn J Dickson, Chris Dockendorff
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 29 Issue 23 Pg. 126681 (12 01 2019) ISSN: 1464-3405 [Electronic] England
• PMID: 31668424 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Ltd. All rights reserved.

Chemical References

• Anthracenes
• KCNQ2 Potassium Channel
• KCNQ2 protein, human
• KCNQ3 Potassium Channel
• KCNQ3 protein, human
• Potassium Channel Blockers
• anthrone

Topics

• Anthracenes (chemical synthesis, chemistry, pharmacology)
• Dose-Response Relationship, Drug
• KCNQ2 Potassium Channel (antagonists & inhibitors, metabolism)
• KCNQ3 Potassium Channel (antagonists & inhibitors, metabolism)
• Mental Disorders (drug therapy)
• Molecular Structure
• Neurodegenerative Diseases (drug therapy)
• Potassium Channel Blockers (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship