Synthesis and Optimization of K7 (KCNQ) Potassium Channel Agonists: The Role of Fluorines in Potency and Selectivity.

Based on the potent K7 agonist , we prepared new lead structures with greatly improved selectivity for K7.2/K7.3 over related potassium channels, i.e., K7.3/K7.5, K7.4, and K7.4/7.5. and maintain an agonist EC of ca. 1 μM on K7.2/K7.3 in a high-throughput assay on an automated electrophysiology platform in HEK293 cells but lack activity on K7.3/K7.5, K7.4, and K7.4/7.5, resulting in a selectivity index SI > 10. is remarkably potent, EC 0.11 ± 0.02 μM, and still shows an SI = 2.5. We also identified analogues with significant selectivity for K7.4/K7.5 over K7.2/K7.3. The extensive use of fluorine in iterative core structure modifications highlights the versatility of these substituents, including F, CF, and SF, to span orders of magnitude of potency and selectivity in medicinal chemistry lead optimizations.