α-Fluorination of tropane compounds and its impact on physicochemical and ADME properties

Bioorg Med Chem Lett. 2024 Aug 1:108:129798. doi: 10.1016/j.bmcl.2024.129798. Epub 2024 May 14.

Abstract

Using an electrochemical C(sp3)-H fluorination reaction, a series of α-fluorinated tropane compounds were synthesized and their druglikeness parameters were assessed to compare with the parent compounds. Improvements were observed in membrane permeability, P-gp liability, and inhibitory effects on hERG and Nav1.5 channels, accompanied with a trend of decreased aqueous solubility and microsomal stability. It was also revealed that α-fluorination reduced the basicity of tropane nitrogen atom for about 1000-fold.

Keywords: C-H functionalization; Electrochemistry; Fluorination.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Animals
  • Cell Membrane Permeability / drug effects
  • Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
  • Ether-A-Go-Go Potassium Channels / metabolism
  • Halogenation*
  • Humans
  • Molecular Structure
  • Solubility*
  • Structure-Activity Relationship
  • Tropanes* / chemical synthesis
  • Tropanes* / chemistry
  • Tropanes* / pharmacology

Substances

  • Tropanes
  • Ether-A-Go-Go Potassium Channels
  • ATP Binding Cassette Transporter, Subfamily B, Member 1