Structure–Activity Relationships of 1,4‐Benzodiazepines Inhibiting the Voltage‐Gated Potassium Channel K _V 7.1

ABSTRACT

K _V 7.1 antagonists hold potential for the treatment of diarrhea, reflux esophagitis, and hypoinsulinemia. The 1,4‐benzodiazepine L768,673 (( R )‐ 1 ) is a potent and selective K _V 7.1 channel blocker with a higher apparent affinity for the K _V 7.1 ion channel than other K _V 7.1 modulators including (R)‐L3. In this study, L768,673 (( R )‐ 1 ) was systematically modified at two positions, and the inhibitory effects of the resulting 1,4‐benzodiazepines were evaluated by two‐electrode voltage‐clamp (TEVC) experiments. Acylation of the primary amines rac ‐ 7 and 9 provided amides 8 and 10a – e . Alkylation of secondary lactam 10a led to tertiary lactams 12a – c . Secondary lactams 10a – e and tertiary lactams 12a , b with large 1‐substituents could not inhibit the K _V 7.1 channel. However, racemic 3‐fluoropropyl derivative 12c was as active as the enantiomerically pure lead compound ( R )‐ 1 rendering 12c an interesting starting point for the development of an 18‐fluorine labeled PET tracer.