Symmetric kv1.5 blockers discovered by focused screening

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Pharmacology

Background:

• Atrial fibrillation treatment requires novel therapeutics targeting ion channels.
• Kv1.5 channels are critical targets for antiarrhythmic drug development.

Purpose of the Study:

• To identify potent Kv1.5 blockers for potential atrial fibrillation treatment.
• To explore structure-activity relationships of novel compounds.

Main Methods:

• Computational methods guided the selection of 1920 compounds from a corporate collection.
• Maximum common substructure similarity-based procedure was used for focused screening.
• Screening focused on identifying inhibitors of Kv1.5 channel activity.

Main Results:

• A focused screen yielded a 12% hit rate.
• A series of potent Kv1.5 blockers featuring a 1,2-diphenylethane-1,2-diamine substructure was identified.
• The identified compounds met lead-optimization criteria.

Conclusions:

• The 1,2-diphenylethane-1,2-diamine series represents a promising starting point for developing new atrial fibrillation treatments.
• These findings provide a foundation for safe and effective antiarrhythmic drug development.