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

Porter JD, Vivas O, Weaver CD, Alsafran A, DiMilo E, Arnold LA, Dickson EJ, Dockendorff C
Bioorg Med Chem Lett. 2019 29 (23): 126681

PMID: 31668424 · PMCID: PMC6858848 · DOI:10.1016/j.bmcl.2019.126681

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 (IC = 0.16 μM in a Kv7.2 thallium flux assay), efficacy in a Kv7.2/7.3 patch clamp assay, and drug-like properties.

Copyright © 2019 Elsevier Ltd. All rights reserved.

MeSH Terms (9)

Anthracenes Dose-Response Relationship, Drug KCNQ2 Potassium Channel KCNQ3 Potassium Channel Mental Disorders Molecular Structure Neurodegenerative Diseases Potassium Channel Blockers Structure-Activity Relationship

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