Structure-Activity Relationship Studies in a Series of Xanthine Inhibitors of SLACK Potassium Channels.

ABSTRACT: Gain-of-function mutations in the KCNT1 gene, which encodes the sodium-activated potassium channel known as SLACK, are associated with the rare but devastating developmental and epileptic encephalopathy known as epilepsy of infancy with migrating focal seizures (EIMFS). The design of small molecule inhibitors of SLACK channels represents a potential therapeutic approach to the treatment of EIMFS, other childhood epilepsies, and developmental disorders. Herein, we describe a hit optimization effort centered on a xanthine SLACK inhibitor (8) discovered via a high-throughput screen. Across three distinct regions of the chemotype, we synthesized 58 new analogs and tested each one in a whole-cell automated patch-clamp assay to develop structure-activity relationships for inhibitio

SUBMITTER: Qunies AM 

PROVIDER: S-EPMC11173529 | biostudies-literature | 2024 May

REPOSITORIES: biostudies-literature