Lipoic acid analogs with enhanced pharmacological activity

A series of lipoic acid analogs, as exemplified by compound 4, was designed, synthesized and evaluated for cytoprotective activity in an ischemia-reperfusion animal model. Lipoic acid (1,2-dithiolane-3-pentanoic acid) is a pharmacophore with unique antioxidant and cytoprotective properties. We synth...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2014-01, Vol.22 (1), p.505-512
Main Authors: Kates, Steven A., Casale, Ralph A., Baguisi, Alexander, Beeuwkes, Reinier
Format: Article
Language:English
Subjects:
Amino acids
Animals
Dipeptides - pharmacology
Disease Models, Animal
Ischemia-reperfusion
Lipoic acid
Magnetic Resonance Spectroscopy
Male
Polymerization
Rats
Rats, Sprague-Dawley
Reperfusion Injury
SAR studies
Structure-Activity Relationship
Thioctic Acid - analogs & derivatives
Thioctic Acid - pharmacology
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Summary:A series of lipoic acid analogs, as exemplified by compound 4, was designed, synthesized and evaluated for cytoprotective activity in an ischemia-reperfusion animal model. Lipoic acid (1,2-dithiolane-3-pentanoic acid) is a pharmacophore with unique antioxidant and cytoprotective properties. We synthesized a library based upon the condensation of natural and unnatural amino acids with the carboxylic acid moiety of lipoic acid. SAR studies were conducted using a cardiac ischemia-reperfusion animal model. Cytoprotective efficacy was associated with the R-enantiomer of the dithiolane. Potency of library compounds was dictated by the acidic strength of the adduct. α-N-[(R)-1,2-dithiolane-3-pentanoyl]-l-glutamyl-l-alanine, designated CMX-2043, was chosen for further pharmacologic evaluation.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2013.10.057