Symmetric Kv1.5 Blockers Discovered by Focused Screening

Guided by computational methods, a set of 1920 compounds were selected from the AstraZeneca corporate collection and screened for Kv1.5 activity. To facilitate rapid generation of structure–activity relationships, special attention was given to selecting subsets of structurally similar molecules by using a maximum common substructure similarity-based procedure. The focused screen hit rate was relatively high (12%). More importantly, a structural series featured by the symmetric 1,2-diphenylethane-1,2-diamine substructure was identified as potent Kv.1.5 blockers. The property profile for the series is shown to meet stringent lead-optimization criteria, providing a springboard for the development of a new and safe treatment for atrial fibrillation.