This invention is a family of fused-ring small molecules built on a 4-aminopiperidine core, designed to modulate Kv7 (KCNQ) potassium channels that regulate how excitable nerve and other cells are. By targeting Kv7 channels, the compounds offer a path to treating a wide range of Kv7-mediated conditions, including epilepsy, pain, tinnitus and neurodegeneration.
Novel chemotypes have been identified that can selectively modulate Kv7 channels. Structure activity relationship studies could result in the development of safe and effective Kv7 modulators to treat a variety of channelopathies.
Description
Unmet Need - Kv7 channel dysfunction is linked to several hard-to-treat neurological conditions, and this new chemical class gives drug developers fresh Kv7-directed molecules to work with.
A six-membered nitrogen-containing ring (a piperidine) is fused to a five-membered heteroaromatic ring that can contain nitrogen, sulfur or oxygen, such as a thiophene, pyrazole or isoxazole. An amine at the 4-position of the piperidine ring carries a carbamate, amide, urea or sulfonamide group. Alkyl, cycloalkyl or aryl groups at the neighboring ring positions, and groups such as alkoxy, halogen, cyano or ester on the five-membered ring, can be varied to tune the compound.
Kv7 channels help set the resting electrical state of cells and control their excitability. The compounds act as modulators of these channels, which are found in the central and peripheral nervous system. The compounds can be provided as stereoisomers, pharmaceutically acceptable salts, solvates or hydrates.
Applications
- Small-molecule therapeutics for epilepsy and developmental or epileptic encephalopathies
- Treatments for pain and tinnitus
- Therapeutics for neurodegeneration, depression, schizophrenia, bipolar disorder and traumatic brain injury
- Treatments for other Kv7-mediated conditions, including cardiovascular disease, cancer, fibromyalgia, arthritis, smooth muscle disorders, erectile dysfunction, myotonia congenita and inflammatory airway diseases
- Starting scaffold for medicinal chemistry programs targeting Kv7 channels
Advantages
- New chemical scaffold directed at Kv7 potassium channels
- Applicable across a broad range of Kv7-mediated disorders spanning neurological, psychiatric, pain, cardiovascular and other conditions
- Highly tunable structure, with multiple positions that can be varied to optimize compounds
- Choice of fused five-membered ring (e.g., thiophene, pyrazole, isoxazole) to diversify the compound series
- Available as stereoisomers, salts, solvates or hydrates, giving formulation flexibility
Invention Readiness
A series of representative compounds has been synthesized and chemically characterized, with reported yields and structural confirmation. The document reports no biological data. Next steps include testing the compounds’ activity on Kv7 channels in in vitro assays, establishing selectivity and mechanism of action, and then moving into disease models, pharmacokinetic profiling and safety studies to identify lead compounds.
IP Status
https://patents.google.com/patent/WO2026035972A1Related Publication(s)
Hernandez, C. C., Tarfa, R. A., Miguel I. Limcaoco, J., Liu, R., Mondal, P., Hill, C., Duncan, K. R., Tzounopoulos, T., Stephenson, C. R. J., O’Meara, M. J., & Wipf, P. (2022). Development of an automated screen for Kv7.2 potassium channels and discovery of a new agonist chemotype. Bioorganic & Medicinal Chemistry Letters, 71, 128841. https://doi.org/10.1016/j.bmcl.2022.128841
Borgini, M., Mondal, P., Liu, R., & Wipf, P. (2021). Chemical modulation of Kv7 potassium channels. RSC Medicinal Chemistry, 12(4), 483–537. https://doi.org/10.1039/d0md00328j
