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
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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