Discovery of Novel Bicyclic Pyrazole Amides as Potent Neuronal KV7 Potassium Channel Openers with Strong Preclinical Antiseizure Activity

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.