Structure–Activity Relationship Study on Ligands Activating the Voltage‐Gated Potassium Channel K V 7.1

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ABSTRACT K V 7.1 agonists are promising therapeutic agents for the treatment of hypertension, arrhythmia and preterm labor. The 3‐(indol‐3‐ylmethyl) substituted 1,4‐benzodiazepine (R)‐L3 has been reported as a potent K V 7.1 activator. In this study, (R)‐L3 was systematically modified at eight positions including the configuration at 3‐position. For the synthesis of the designed 1,4‐benzodiazepines 8 and 12 , 2‐aminobenzophenones 4 were reacted with amino acid derived 1,3‐oxazolidinediones 7 or 11 . The required 2‐aminobenzophenones 4 were obtained regioselectively by Sugasawa reaction of anilines 2 and 3 with various substituted benzonitriles, using BCl 3 and AlCl 3 . Racemization during deprotonation and alkylation of secondary lactams 8 and 12 was not observed. However, racemization occurred during conversion of lactam 8b into thiolactam 17 . The enantiomers of thiolactam rac ‐ 17 and triazole rac ‐ 18 were separated by chiral HPLC. The ion channel modulatory activity of the resulting 1,4‐benzodiazepines was evaluated by two‐electrode voltage‐clamp (TEVC) experiments. These TEVC experiments showed that (3 R )‐configuration and the indolylmethyl moiety at 3‐position are essential for K V 7.1 activation. High activity was observed for secondary lactam 8b and methylated lactam 9b , but larger N‐substituents reduced the channel activation. The thioamide ( R )‐ 17 and the triazole ( R )‐ 18 did not significantly activate the K V 7.1 channel. Replacement of the F‐atom in 2‐position of the 5‐phenyl moiety by a proton or other halogen atoms reduced the K V 7.1 activity. However, the 9‐hydroxy derivative 9i appeared to exhibit higher agonistic activity (+68% activity increase at 1 µM) than (R)‐L3 ( 9b , +45% at 1 µM). Moreover, higher phase I metabolic stability was observed for phenol 9i .

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