A University of Pittsburgh researcher has identified novel modulators for the Kv7 potassium channels. Substituted 5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-8-amine and 5,6,7,8-tetrahydropyrido[3,2-e][1,2,4]triazin-5-amine scaffolds have been identified as novel chemotypes capable of selectively modulating Kv7 activity. Successful development of medications to target Kv7 potassium channels could dramatically improve the lives of patients with various channelopathies including pain, epilepsy, tinnitus, cardiovascular disease, and cancer.
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
Kv7 is a potassium channel family of transmembrane proteins that contribute to the maintenance of the resting membrane potential and the control of cell excitability in cells. Encoded by KCNQ genes, of which 5 isoforms exist (Kv7.1-5), mutations are implicated in several disorders such as epilepsy. The Kv7.2 isoform is implicated in epilepsy and tinnitus and there is a need to develop isoform-specific chemical probes and agonists (or antagonists) to better understand channel dynamics and modulate channel activity. Two novel chemotypes that can selectively bind to Kv7.2 channel isoforms have been identified which offers an approach using structure activity relationship studies to optimize and develop novel treatments for channelopathies.
Applications
• Tinnitus
• Epilepsy
• Channelopathies including cardiovascular disease and neurodegeneration
Advantages
Kv7 agonists were previously approved for use in the USA and Europe but were discontinued due to adverse events that included blue skin discoloration and liver damage.
These novel modulators have been identified using a newly developed automated screen. In silico studies predict these compounds bind in Kv7 channels in a different arrangement to previously approved compounds, modulating Kv7 activity. This difference in binding geometry could mean these novel compounds may be less likely to result in adverse events previously observed in Kv7 modulators.
Invention Readiness
Screening studies of 22 compounds against Kv7.2 wild type (WT) and W236L mutant channels identified several compounds that selectively enhanced activity in WT channels. One compound of note, ZK-21, was found to exhibit differential enhancing activity between WT and W236L mutant channels comparable with retigabine and flupirtine, previously approved Kv7 agonists. ZK-21 has an EC50=2.2 M in WT channels suggesting derivatives could be promising new agonists. In silico docking studies suggest ZK-21 binds differently to retigabine and is stabilized by the presence of W236. Further structure activity relationship studies are required to develop optimal modulators for Kv7 channels.
IP Status
https://patents.google.com/patent/WO2025034745A1
