Synthesis and screening of chromanol 293B analogues identified HMR1556 as a highly active and selective IKs-channel blocker for development as an antiarrhythmic drug.
HMR1556 was identified as a potent and selective IKs-channel blocker for potential development as an antiarrhythmic drug.
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 search 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 was 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 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.
Gerlach et al. (Thu,) conducted a other in Arrhythmia (preclinical model). Chromanol 293B and HMR1556 was evaluated on IKs-channel blocking activity. Synthesis and screening of chromanol 293B analogues identified HMR1556 as a highly active and selective IKs-channel blocker for development as an antiarrhythmic drug.