title: Symmetric kv1.5 blockers discovered by focused screening.
abstract: 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.
authors.affiliation: AstraZeneca R&D Mölndal , CVGI iMed, S-431 83 Mölndal, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Boström
keywords: Kv1.5 blockers; atrial fibrillation; focused screen; maximum common substructure; structural series; symmetric ligands