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An Anthrone-Based Kv7.2/7.3 Channel Blocker with Improved Properties for the Investigation of Psychiatric and Neurodegenerative Disorders

10 June 2019, Version 1
Working Paper
This content is a preprint and has not undergone peer review at the time of posting.

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 (JDP-107) with an optimal 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

voltage-gated potassium channel
Kv7
KCNQ2/3
channel blocker
schizophrenia
Parkinson's Disease
anthrone derivatives
DMP 543
XE991
JDP-107

Supplementary materials

Title
Description
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Title
2019 06 08 Kv7 blockers ChemRxiv SI
Description
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Now Published

An anthrone-based Kv7.2/7.3 channel blocker with improved properties for the investigation of psychiatric and neurodegenerative disorders [opens in a new tab]
Jacob D. Porter, Oscar Vivas, C. David Weaver, Abdulmohsen Alsafran, Elliot DiMilo, Leggy A. Arnold, Eamonn J. Dickson, Chris Dockendorff journal article
Bioorganic & Medicinal Chemistry Letters , Volume 29, Issue 23
Print publication date: Dec, 2019

Version History

Jun 10, 2019 Version 1

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The content is available under CC BY NC ND 4.0 [opens in a new tab]

DOI

10.26434/chemrxiv.8246417.v1
D O I: 10.26434/chemrxiv.8246417.v1 [opens in a new tab]

Funding

NIGMS R01GM127513

Author’s competing interest statement

C.D.W. is an owner of WaveFront Biosciences and ION Biosciences, manufacturers of the Panoptic plate reader and thallium-sensitive dyes used for the thallium flux assays described in this manuscript.

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