Orale Antidiabetika

Glombik, Von Heiner; Weyer, R. Vande

doi:10.1007/978-3-0348-9311-4_9

Cited by 1 publication

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“…In contrast, glibenclamide acts on both types of K ATP channels suggesting that the methoxychlorobenzamide moiety is a good option to achieve additional cardiac activity since tolbutamide lacks this structural feature. On the other hand, a bulky lipophilic substituent attached to the terminal nitrogen of the sulfonylurea moiety is present in both compounds and in addition is a key structural feature of all other antidiabetic sulfonylureas known so far . In the following we focused on structural variations of glibenclamide-like molecules keeping the methoxychlorobenzamide moiety unchanged and, in addition, tried to reduce the size of the lipophilic substituent at the sulfonylurea moiety.…”

Section: Introductionmentioning

confidence: 99%

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

Englert¹,

Gerlach²,

Goegelein³

et al. 2001

J. Med. Chem.

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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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Section: Introductionmentioning

confidence: 99%

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

Englert¹,

Gerlach²,

Goegelein³

et al. 2001

J. Med. Chem.

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Orale Antidiabetika

Cited by 1 publication

References 85 publications

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

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

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Orale Antidiabetika

Cited by 1 publication

References 85 publications

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

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

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

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