Synthesis and activity of novel and selective I-Ks-channel blockers

Since the discovery of the I-Ks-potassium channel as the slowly activating component of the delayed rectifier current (I-k) in cardiac tissue, the sea rch for blockers of this current has been intense. During the screening of K-ATP-channel openers of the chromanol type we found that chromanol 293B wa s able to block I-Ks. Chromanol 293B is a sulfonamide analogue of the K-ATP -channel openers but had no activity on this target. Experiments were initi ated to improve the activity and properties based on this lead compound. As a screening model we used Xenopus oocytes injected with human minK (KCNE1) . Variations of the aromatic substituent and the sulfonamide group were pre pared, and their activity was evaluated. We found that the greatest influen ce on activity was found in the aromatic substituents. The most active comp ounds were alkoxy substituted. We chose HMR1556 ((3R, 4S)-(+)-N-[-3-hydroxy -2,2-dimethyl-6-(4,4,4-trifluorobutoxy)chroman-4-yl]-N-methyl-ethanesulfona mide) 10a for development as an antiarrhythmic drug. The absolute configura tion, resulting from an X-ray single-crystal structure analysis, was determ ined.