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An anthrone-based Kv7.2/7.3 channel blocker with improved properties for the investigation of psychiatric and neurodegenerative disorders.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2019 Dec 01; Vol. 29 (23), pp. 126681. Date of Electronic Publication: 2019 Sep 14. - Publication Year :
- 2019
-
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 <subscript>50</subscript> = 0.16 μM in a Kv7.2 thallium flux assay), efficacy in a Kv7.2/7.3 patch clamp assay, and drug-like properties.<br /> (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 29
- Issue :
- 23
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 31668424
- Full Text :
- https://doi.org/10.1016/j.bmcl.2019.126681