Novel, Non-acylguanidine-type Na+/H+ Exchanger Inhibitors:  Synthesis and Pharmacology of 5-Tetrahydroquinolinylidene Aminoguanidine Derivatives

In the course of our research into new types of non-acylguanidine Na+/H+ exchanger (NHE) inhibitors, we designed and synthesized aryl-fused tetrahydropyranylidene and cyclohexylidene aminoguanidine derivatives I (X = O, CH2), which were tested for their inhibitory effects on rat platelet NHEs. After...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2002-07, Vol.45 (14), p.3009-3021
Main Authors: Fukumoto, Shoji, Imamiya, Eiko, Kusumoto, Keiji, Fujiwara, Shuji, Watanabe, Toshifumi, Shiraishi, Mitsuru
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Blood Platelets - drug effects
Blood Platelets - metabolism
Cardiovascular Agents - chemical synthesis
Cardiovascular Agents - chemistry
Cardiovascular Agents - pharmacology
Cardiovascular system
Crystallography, X-Ray
Guanidines - chemical synthesis
Guanidines - chemistry
Guanidines - pharmacology
Humans
Male
Medical sciences
Miscellaneous
Molecular Structure
Myocardial Infarction - pathology
Pharmacology. Drug treatments
Quinolines - chemical synthesis
Quinolines - chemistry
Quinolines - pharmacology
Rats
Rats, Wistar
Sodium-Hydrogen Exchangers - antagonists & inhibitors
Stereoisomerism
Structure-Activity Relationship
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Summary:In the course of our research into new types of non-acylguanidine Na+/H+ exchanger (NHE) inhibitors, we designed and synthesized aryl-fused tetrahydropyranylidene and cyclohexylidene aminoguanidine derivatives I (X = O, CH2), which were tested for their inhibitory effects on rat platelet NHEs. After optimization, we found that the S isomer of tetrahydroquinoline derivatives that possess a methyl group in the 4-position and a halogen or methyl group in the o-position of Ar2 exhibited high inhibitory activity. In these compounds, (5E,7S)-[[7-(5-fluoro-2-methylphenyl)-4-methyl-7,8-dihydro-5(6H)-quinolinylidene]amino]guanidine dimethanesulfonate (18, T-162559) was found to be a potent inhibitor of both rat and human platelet NHEs, with IC50 values of 14 and 13 nM, respectively. Furthermore, in a rat myocardial infarction model in vivo (1 h ischemia−24 h reperfusion), 18 (0.1 mg/kg, intravenously administered 5 min or 2 h before coronary occlusion) showed significant activity (33% or 23% inhibition, respectively). These results suggested that 18 may exhibit a potent and long-lasting protective activity against cardiac injuries induced by ischemia−reperfusion.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm0104567