1. An anthrone-based Kv7.2/7.3 channel blocker with improved properties for the investigation of psychiatric and neurodegenerative disorders.
- Author
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Porter JD, Vivas O, Weaver CD, Alsafran A, DiMilo E, Arnold LA, Dickson EJ, and Dockendorff C
- Subjects
- Anthracenes chemical synthesis, Anthracenes chemistry, Dose-Response Relationship, Drug, KCNQ2 Potassium Channel metabolism, KCNQ3 Potassium Channel metabolism, Molecular Structure, Potassium Channel Blockers chemical synthesis, Potassium Channel Blockers chemistry, Structure-Activity Relationship, Anthracenes pharmacology, KCNQ2 Potassium Channel antagonists & inhibitors, KCNQ3 Potassium Channel antagonists & inhibitors, Mental Disorders drug therapy, Neurodegenerative Diseases drug therapy, Potassium Channel Blockers pharmacology
- 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 (IC
50 = 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.)- Published
- 2019
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