Bicyclic Acylguanidine Na+/H+ Antiporter Inhibitors

Blockade of the Na+/H+ exchange has been shown to diminish the serious consequences of myocardial ischemia. The aim of this investigation was to alter the structure of the common benzoylguanidine NHE inhibitors in such a way that the 3-methylsulfonyl and 4-alkyl group form a ring. The new benz-fused...

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Veröffentlicht in:Journal of medicinal chemistry 1998-09, Vol.41 (19), p.3736-3747
Hauptverfasser: Baumgarth, Manfred, Beier, Norbert, Gericke, Rolf
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container_issue 19
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container_title Journal of medicinal chemistry
container_volume 41
creator Baumgarth, Manfred
Beier, Norbert
Gericke, Rolf
description Blockade of the Na+/H+ exchange has been shown to diminish the serious consequences of myocardial ischemia. The aim of this investigation was to alter the structure of the common benzoylguanidine NHE inhibitors in such a way that the 3-methylsulfonyl and 4-alkyl group form a ring. The new benz-fused five-, six-, and seven-membered ring sulfones were prepared by internal Heck reaction. Benz-fused five-membered ring sulfones could also be prepared by internal aldol-type condensation using ketones or nitriles as acceptor groups. In the final step, the carboxyl groups were converted to acylguanidines preferentially by guanidine treatment of the esters or acid chlorides. The compounds were tested as their methanesulfonate salts. The inhibition of the Na+/H+ antiport activity was determined by observing the uptake of 22Na+ into acidified rabbit erythrocytes. Additionally, the inhibition of the antiport activity was assessed also by the platelet swelling assay (PSA), in which the swelling of human platelets was induced by the incubation in the presence of a weak organic acid. On average, the IC50 values in the PSA turned out to be about 10-fold higher than in the erythrocyte assay primarily due to a higher Na+ concentration in the PSA; however, the order of the compounds' potency was not substantially altered. The new compounds were found to be highly active with peak values ranging within the cariporide and EMD 96785 standards.
doi_str_mv 10.1021/jm981031w
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On average, the IC50 values in the PSA turned out to be about 10-fold higher than in the erythrocyte assay primarily due to a higher Na+ concentration in the PSA; however, the order of the compounds' potency was not substantially altered. 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Med. Chem</addtitle><description>Blockade of the Na+/H+ exchange has been shown to diminish the serious consequences of myocardial ischemia. The aim of this investigation was to alter the structure of the common benzoylguanidine NHE inhibitors in such a way that the 3-methylsulfonyl and 4-alkyl group form a ring. The new benz-fused five-, six-, and seven-membered ring sulfones were prepared by internal Heck reaction. Benz-fused five-membered ring sulfones could also be prepared by internal aldol-type condensation using ketones or nitriles as acceptor groups. In the final step, the carboxyl groups were converted to acylguanidines preferentially by guanidine treatment of the esters or acid chlorides. The compounds were tested as their methanesulfonate salts. The inhibition of the Na+/H+ antiport activity was determined by observing the uptake of 22Na+ into acidified rabbit erythrocytes. Additionally, the inhibition of the antiport activity was assessed also by the platelet swelling assay (PSA), in which the swelling of human platelets was induced by the incubation in the presence of a weak organic acid. On average, the IC50 values in the PSA turned out to be about 10-fold higher than in the erythrocyte assay primarily due to a higher Na+ concentration in the PSA; however, the order of the compounds' potency was not substantially altered. 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Drug treatments</topic><topic>Rabbits</topic><topic>Sodium - metabolism</topic><topic>Sodium-Hydrogen Exchangers - antagonists &amp; inhibitors</topic><topic>Structure-Activity Relationship</topic><topic>Sulfones - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Baumgarth, Manfred</creatorcontrib><creatorcontrib>Beier, Norbert</creatorcontrib><creatorcontrib>Gericke, Rolf</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Baumgarth, Manfred</au><au>Beier, Norbert</au><au>Gericke, Rolf</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Bicyclic Acylguanidine Na+/H+ Antiporter Inhibitors</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. 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subjects Animals
Antiarythmic agents
Biological and medical sciences
Blood Platelets - cytology
Blood Platelets - drug effects
Cardiovascular system
Cell Size - drug effects
Erythrocytes - drug effects
Erythrocytes - metabolism
Guanidines - chemical synthesis
Guanidines - chemistry
Guanidines - pharmacology
Humans
In Vitro Techniques
Medical sciences
Pharmacology. Drug treatments
Rabbits
Sodium - metabolism
Sodium-Hydrogen Exchangers - antagonists & inhibitors
Structure-Activity Relationship
Sulfones - pharmacology
title Bicyclic Acylguanidine Na+/H+ Antiporter Inhibitors
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