Structure-Activity Relationships for the N-Me- Versus N-H-Amide Modification to Macrocyclic ent-Verticilide Antiarrhythmics

Abigail N. Smith, Madelaine P. Thorpe, Daniel J. Blackwell, Suzanne M. Batiste, Corey R. Hopkins, Nathan D. Schley, Bjorn C. Knollmann, Jeffrey N. Johnston

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

The synthesis of all N-Me and N-H analogues of ent-verticilide is described, enabling a structure-activity relationship study based on cardiac ryanodine receptor (RyR2) calcium ion channel inhibition. The use of permeabilized cardiomyocytes allowed us to correlate the degree of N-methylation with activity without concern for changes in passive membrane permeability that these modifications can cause. A key hypothesis was that the minimal pharmacophore may be repeated in this cyclic oligomeric octadepsipeptide (a 24-membered macrocycle), opening the possibility that target engagement will not necessarily be lost with a single N-Me → N-H modification. The effect in the corresponding 18-membered ring oligomer (ent-verticilide B1) was also investigated. We report here that a high degree of N-methyl amide content is critical for activity in the ent-verticilide series but not entirely so for the ent-verticilide B1 series.

Original languageEnglish (US)
Pages (from-to)1755-1762
Number of pages8
JournalACS Medicinal Chemistry Letters
Volume13
Issue number11
DOIs
StatePublished - Nov 10 2022

Keywords

  • arrhythmia
  • calcium ion channel
  • depsipeptide
  • ring-size analogue
  • ryanodine receptor
  • tertiary amide

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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