Synthesis and Optimization of Kv7 (KCNQ) Potassium Channel Agonists: The Role of Fluorines in Potency and Selectivity.

Based on the potent Kv7 agonist RL-81, we prepared new lead structures with greatly improved selectivity for Kv7.2/Kv7.3 over related potassium channels, i.e., Kv7.3/Kv7.5, Kv7.4, and Kv7.4/7.5. RL-36 and RL-12 maintain an agonist EC2x of ca. 1 μM on Kv7.2/Kv7.3 in a high-throughput assay on an automated electrophysiology platform in HEK293 cells but lack activity on Kv7.3/Kv7.5, Kv7.4, and Kv7.4/7.5, resulting in a selectivity index SI > 10. RL-56 is remarkably potent, EC2x 0.11 ± 0.02 μM, and still shows an SI = 2.5. We also identified analogues with significant selectivity for Kv7.4/Kv7.5 over Kv7.2/Kv7.3. The extensive use of fluorine in iterative core structure modifications highlights the versatility of these substituents, including F, CF3, and SF5, to span orders of magnitude of potency and selectivity in medicinal chemistry lead optimizations.