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

preprint
submitted on 08.06.2019 and posted on 10.06.2019 by Jacob Porter, Oscar Vivas-Rodriguez, C. David Weaver, Eamonn Dickson, Abdulmohsen Alsafran, Elliot DiMilo, Leggy Arnold, Chris Dockendorff
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.

Funding

NIGMS R01GM127513

History

Email Address of Submitting Author

christopher.dockendorff@mu.edu

Institution

Marquette University

Country

United States

ORCID For Submitting Author

0000-0002-4092-5636

Declaration of Conflict of Interest

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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