| Autor: |
Mishra NM; Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA., Spitznagel BD; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA., Du Y; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA., Mohamed YK; Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA., Qin Y; Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.; College of Biomedical and Translational Sciences, University of North Texas Health Science Center, Fort Worth, TX 76107, USA., Weaver CD; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA., Emmitte KA; Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA. |
| Abstrakt: |
Epilepsy of infancy with migrating focal seizures (EIMFS) is a rare, serious, and pharmacoresistant epileptic disorder often linked to gain-of-function mutations in the KCNT1 gene. KCNT1 encodes the sodium-activated potassium channel known as SLACK, making small molecule inhibitors of SLACK channels a compelling approach to the treatment of EIMFS and other epilepsies associated with KCNT1 mutations. In this manuscript, we describe a hit optimization effort executed within a series of 2-aryloxy- N -(pyrimidin-5-yl)acetamides that were identified via a high-throughput screen. We systematically prepared analogs in four distinct regions of the scaffold and evaluated their functional activity in a whole-cell, automated patch clamp (APC) assay to establish structure-activity relationships for wild-type (WT) SLACK inhibition. Two selected analogs were also profiled for selectivity versus other members of the Slo family of potassium channels, of which SLACK is a member, and versus a panel of structurally diverse ion channels. The same two analogs were evaluated for activity versus the WT mouse channel as well as two clinically relevant mutant human channels. |
