Synthesis and Activity of Novel and Selective IKs-Channel Blockers

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Abstract
Since the discovery of the IKs-potassium channel as the slowly activating component of the delayed rectifier current (Ik) in cardiac tissue, the search for blockers of this current has been intense. During the screening of KATP-channel openers of the chromanol type we found that chromanol 293B was able to block IKs. Chromanol 293B is a sulfonamide analogue of the KATP-channel openers but had no activity on this target. Experiments were initiated 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 prepared, and their activity was evaluated. We found that the greatest influence on activity was found in the aromatic substituents. The most active compounds were alkoxy substituted. We chose HMR1556 ((3R, 4S)-(+)-N-[-3-hydroxy-2,2-dimethyl-6-(4,4,4-trifluorobutoxy)chroman-4-yl]-N-methyl-ethanesulfonamide) 10a for development as an antiarrhythmic drug. The absolute configuration, resulting from an X-ray single-crystal structure analysis, was determined.