Discovery of Novel Bicyclic Pyrazole Amides as Potent Neuronal KV7 Potassium Channel Openers with Strong Preclinical Antiseizure Activity
Year: 2026
Type: article
Abstract: There has been considerable interest in developing openers of neuronal KV7 potassium channels, particularly KV7.2 (KCNQ2) and KV7.3 (KCNQ3), as both genetic and clinical evidence strongly support their therapeutic potential in seizure disorders. Herein, we describe the discovery of a series of neuronal KV7 potassium channel openers, optimized primarily via conformational rigidification and carbon to oxygen replacement. The combination of these structural modifications, together with careful investigation of the structure–activity relationship (SAR), culminated in the discovery of S-35, a potent and metabolically stable neuronal KV7 opener that demonstrated favorable pharmacokinetics (PK) in preclinical species and robust antiseizure efficacy in rodent alternating-current maximal electroshock seizure (AC-MES) assays.
Source: ACS Medicinal Chemistry Letters
Authors: Shaoyi Sun, Qi Jia, Girish Bankar, Kristen N. Burford, Jessica Christabel, Helen A. Clement, Gina de Boer, Zirui Feng, Chido M. Hambira, Stephen K. Jackson, Kuldip Khakh, Rainbow Kwan, Stephanie Lee, Jenny Li, Andrea Lindgren, Janette Mezeyova, Juliette Sabbatini, Art Urrutia, Paul Charifson, Michael P. Clark, Steven S. Wesolowski, James P. Johnson, James R. Empfield, Christoph M. Dehnhardt, Richard Dean
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7204088419