Abstract
Sulfonylthioureas exhibiting cardioselective blockade of ATP-sensitive potassium channels (K(ATP) channels) were discovered by stepwise structural variations of the antidiabetic sulfonylurea glibenclamide. As screening assays, reversal of rilmakalim-induced shortening of the cardiac action potential in guinea pig papillary muscles was used to probe for activity on cardiac K(ATP) channels as the target, and membrane depolarization in CHO cells stably transfected with hSUR1/hKir6.2 was used to probe for unwanted side effects on pancreatic K(ATP) channels. Changing glibenclamide's para-arrangement of substituents in the central aromatic ring to a meta-pattern associated with size reduction of the substituent at the terminal nitrogen atom of the sulfonylurea moiety was found to achieve cardioselectivity. An additional change from a sulfonylurea moiety to a sulfonylthiourea moiety along with an appropriate substituent in the ortho-position of the central aromatic system was a successful strategy to further improve potency on the cardiac K(ATP) channel. Among this series of sulfonylthioureas HMR1883, 1-[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl-3-methylthiourea, and its sodium salt HMR1098 were selected for development and represent a completely new therapeutic approach toward the prevention of life-threatening arrhythmias and sudden cardiac death in patients with coronary heart disease.
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