Synthesis and analysis of novel glycerolipids for the treatment of metabolic syndrome.
Tetradecylthioacetic acid (TTA) 1 is a peroxisome proliferator-activated receptor (PPAR) agonist found to improve insulin sensitivity, lower blood lipid levels, enhance fatty acid oxidation, and promote anti-inflammation in vivo. In an attempt to enhance these properties, two key thioether fatty acid (Thefa) lipids, ditetradecylthioacetyl phosphatidylcholine 2 and tritetradecylthioacetyl glycerol 3, are synthesized and administered po to male Wistar rats at two different doses to study and compare metabolic outcomes relative to the administration of 1 alone after 6 days. Liposomal formulations of 1 and 2 are also prepared to evaluate acute metabolic responses (at 3 h) post i.v. injection. Across all metrics measured, 1-induced responses post po administration are in line with previous data. Responses induced from 3 are mostly equivalent to 1-induced responses. By contrast, 2-induced responses almost always outperform those of 1 and 3. Therefore, 2 may represent a new lead for the treatment of metabolic syndrome.
Jorgensen
Michael R
MR
Imperial College Genetic Therapies Centre, Department of Chemistry, Flowers Building, Armstrong Road, Imperial College London, London SW7 2AZ, United Kingdom.
Bhurruth-Alcor
Yushma
Y
Røst
Therese
T
Bohov
Pavol
P
Müller
Melanie
M
Guisado
Cristina
C
Kostarelos
Kostas
K
Dyrøy
Endre
E
Berge
Rolf K
RK
Miller
Andrew D
AD
Skorve
Jon
J
D000818:Animals; D005989:Glycerides / Q000737:chemistry* / Q000494:pharmacology; D005990:Glycerol; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy*; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists*; D010713:Phosphatidylcholines; D051381:Rats; D017208:Rats, Wistar; D013440:Sulfides / Q000737:chemistry* / Q000494:pharmacology
D005989:Glycerides; D047492:Peroxisome Proliferator-Activated Receptors; D010713:Phosphatidylcholines; D013440:Sulfides; C062078:1-(carboxymethylthio)tetradecane; D005990:Glycerol