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

Ruiting Liu; Thanos Tzounopoulos; Peter Wipf

doi:10.1021/acsmedchemlett.9b00097

Synthesis and Optimization of K_v7 (KCNQ) Potassium Channel Agonists: The Role of Fluorines in Potency and Selectivity

ACS Med Chem Lett. 2019 May 8;10(6):929-935. doi: 10.1021/acsmedchemlett.9b00097. eCollection 2019 Jun 13.

Authors

Ruiting Liu¹, Thanos Tzounopoulos², Peter Wipf¹

Affiliations

¹ Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States.
² Department of Otolaryngology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States.

Abstract

Based on the potent K_v7 agonist RL-81, we prepared new lead structures with greatly improved selectivity for K_v7.2/K_v7.3 over related potassium channels, i.e., K_v7.3/K_v7.5, K_v7.4, and K_v7.4/7.5. RL-36 and RL-12 maintain an agonist EC_2x of ca. 1 μM on K_v7.2/K_v7.3 in a high-throughput assay on an automated electrophysiology platform in HEK293 cells but lack activity on K_v7.3/K_v7.5, K_v7.4, and K_v7.4/7.5, resulting in a selectivity index SI > 10. RL-56 is remarkably potent, EC_2x 0.11 ± 0.02 μM, and still shows an SI = 2.5. We also identified analogues with significant selectivity for K_v7.4/K_v7.5 over K_v7.2/K_v7.3. 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.