Cardioselective KATP Channel Blockers Derived from a New Series of m-Anisamidoethylbenzenesulfonylthioureas

Sulfonylthioureas exhibiting cardioselective blockade of ATP-sensitive potassium channels (KATP 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 KATP 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 KATP 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 p...