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

Bioorg Med Chem Lett. 2019 Dec 1;29(23):126681. doi: 10.1016/j.bmcl.2019.126681. Epub 2019 Sep 14.

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 (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: DMP 543; JDP-107; Kv7 blocker; Schizophrenia; Voltage-gated potassium channel.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anthracenes / chemical synthesis
  • Anthracenes / chemistry
  • Anthracenes / pharmacology*
  • Dose-Response Relationship, Drug
  • KCNQ2 Potassium Channel / antagonists & inhibitors*
  • KCNQ2 Potassium Channel / metabolism
  • KCNQ3 Potassium Channel / antagonists & inhibitors*
  • KCNQ3 Potassium Channel / metabolism
  • Mental Disorders / drug therapy*
  • Molecular Structure
  • Neurodegenerative Diseases / drug therapy*
  • Potassium Channel Blockers / chemical synthesis
  • Potassium Channel Blockers / chemistry
  • Potassium Channel Blockers / pharmacology*
  • Structure-Activity Relationship

Substances

  • Anthracenes
  • KCNQ2 Potassium Channel
  • KCNQ2 protein, human
  • KCNQ3 Potassium Channel
  • KCNQ3 protein, human
  • Potassium Channel Blockers
  • anthrone