Abstract
A series of (5-arylfuran-2-ylcarbonyl)guanidines was synthesized and evaluated for the NHE-1 inhibitory activity and cardiprotective efficacy against ischemia-reperfusion injury. Starting with (5-phenylfuran-2-ylcarbonyl)guanidine 47 with a moderate inhibitory effect on NHE-1, the compounds with various substituents at the phenyl ring were investigated with the aim to optimize the potency. In this study, the 2,5-disubstituted compounds appeared to have better activities than the other analogues, and the 2-methoxy-5-chlorophenyl compound 85 was found as a potent inhibitor of NHE-1 (IC(50) = 0.081 microM). Furthermore, 85 showed a marked reduction of infarct size in the rat myocardial infarction model in vivo and significant improvement of cardiac contractile function in the isolated rat heart ischemia model in vitro.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cardiotonic Agents / chemical synthesis*
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Cardiotonic Agents / chemistry
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Cardiotonic Agents / pharmacology
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Cation Transport Proteins / antagonists & inhibitors
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Cell Line
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Furans / chemical synthesis*
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Furans / chemistry
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Furans / pharmacology
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Guanidines / chemical synthesis*
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Guanidines / chemistry
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Guanidines / pharmacology
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Humans
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In Vitro Techniques
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Membrane Proteins / antagonists & inhibitors
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Myocardial Infarction / drug therapy
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Myocardial Infarction / pathology
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Protein Isoforms / antagonists & inhibitors
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Rats
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Sodium-Hydrogen Exchanger 1
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Sodium-Hydrogen Exchangers / antagonists & inhibitors*
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Structure-Activity Relationship
Substances
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Cardiotonic Agents
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Cation Transport Proteins
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Furans
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Guanidines
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Membrane Proteins
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Protein Isoforms
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SLC9A1 protein, human
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Sodium-Hydrogen Exchanger 1
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Sodium-Hydrogen Exchangers
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(5-(2-methoxy-5-chloro-5-phenyl)furan-2-ylcarbonyl)guanidine