Lead Optimization of Positive Allosteric K_V7.2/3 Channel Modulators toward Improved Balance of Lipophilicity and Aqueous Solubility

The voltage-gated potassium channel K_V7.2/3 is gaining attention for its association with several medical indications. While recently reported, potent compounds aimed to fill the therapeutic gap left by market-withdrawn activators, key physicochemical parameters did not meet the requirements of potential drug candidates. Targeting the membrane-located channel requires subtly balancing lipophilicity, activity, and aqueous solubility. This publication describes the lead optimization of a highly active compound toward optimized physicochemical parameters. Out of 42 newly synthesized compounds, 30 showed activity on K_V7.2/3 channels, and 15 had also an increased solubility compared the to hit compound. The integration of a three-dimensional bulky structure and the probable onset of chameleonic behavior, led to a 20-fold solubility increase (<i>S</i> = 21.7 vs 1.1 μM) and only slightly reduced potency (pEC₅₀ = 7.42 vs 7.96) for the lead. Additionally, the target engagement of the compound was theoretically enhanced by a reduction of membrane retention.