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

The synthesis of all -Me and -H analogues of -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 -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 -Me → -H modification. The effect in the corresponding 18-membered ring oligomer (-verticilide B1) was also investigated. We report here that a high degree of -methyl amide content is critical for activity in the -verticilide series but not entirely so for the -verticilide B1 series.