Structure-Activity Relationships for the <i>N</i>-Me- Versus <i>N</i>-H-Amide Modification to Macrocyclic <i>ent</i>-Verticilide Antiarrhythmics.
Basic Information
ID: ALA5126670
Journal: ACS Med Chem Lett
Title: Structure-Activity Relationships for the N-Me- Versus N-H-Amide Modification to Macrocyclic ent-Verticilide Antiarrhythmics.
Authors: Smith AN, Thorpe MP, Blackwell DJ, Batiste SM, Hopkins CR, Schley ND, Knollmann BC, Johnston JN.
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.
CiteXplore: 36385927
DOI: 10.1021/acsmedchemlett.2c00377
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