Lead Optimization of Positive Allosteric KV7.2/3 Channel Modulators toward Improved Balance of Lipophilicity and Aqueous Solubility
Jana Lemke, Nadine Mengers, Louis Schmidt, Lukas Schulig, Stefanie König, P. L. Rosendahl, Frieda‐Marie Bartz, Ulrike Garscha, Patrick J. Bednarski, Andreas Link · Journal of Medicinal Chemistry · 2025
The voltage-gated potassium channel K V 7.2/3 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 While recently reported, potent compounds aimed to fill the therapeutic gap left by market-withdrawn activators, key physicochemical parameters did not meet the requirements of potential drug candidates.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 V 7.2/3 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 ( S = 21.7 vs 1.1 μM) and only slightly reduced potency (pEC 50 = 7.42 vs 7.96) for the lead. Additionally, the target engagement of the compound was theoretically enhanced by a reduction of membrane retention.