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

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.

Modulators of Ion Channels Activated by Hypotonic Swelling in Cardiomyocytes: New Perspectives for Pharmacological Treatment of Life-Threatening Arrhythmias

“…There is one highly selective compound obtained by modification of the sulphonylurea substance glibenclamide. It is HMR 1883 (chemical name: 1-[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl-3-methylthiourea) and its sodium salt HMR 1098 [48,49].…”

Animal models of lethal arrhythmias

“…The sulfonylthiourea drug HMR 1883 and its sodium salt HMR 1098 were recently developed to block the cardiac ATP-sensitive potassium channel [Englert et al, 2001]. HMR 1883 inhibited the sarcolemmal cardiac ATP-sensitive potassium channel activated by the channel opener rilmakalin at a much lower concentration (guinea pig myocytes IC 50 = 0.6-2.2 µM) than was required to promote insulin release (9-50-fold higher concentration was required to block pancreatic RIN m5F cells) [Gögelein et al, 1998].…”

Current and Emerging Antiarrhythmic Drug Therapy for Ventricular Tachycardia

“…For ATP-sensitive potassium channel inhibition to become an attractive therapeutic option, cardioselective pharmaceuticals must be developed and tested. Currently, the agents HMR-1883, HMR-1098 and HMR-1402 have been developed and studied in animals, with favorable results on the reduction of ischemic cardiac arrhythmias [77]. …”