A cardioselective, hydrophilic N,N,N-trimethylethanaminium alpha-tocopherol analogue that reduces myocardial infarct size.
The alpha-tocopherol analogue 3,4-dihydro-6-hydroxy-N,N,N,2,5,7,8- heptamethyl-2H-1-benzopyran-2-ethanaminium 4-methylbenzenesulfonate (1a, MDL 73404) and its O-acetate 1b (MDL 74270) were synthesized. Compound 1a was found to be hydrophilic (log P = -0.60) and to prevent lipid autoxidation in rat brain homogenate with an IC50 of 1.7 +/- 0.9 microM. Tissue distribution studies with [14C]-1b in rats (1 mg/kg iv) showed that radioactivity accumulates in the heart (ratio 20:1 vs blood after 1 h). Infusion of 1 mg/kg per h of 1b bromide reduced infarct size by 54% in rats subjected to coronary artery occlusion for 60 min followed by reperfusion for 30 min, compared to saline-infused controls. By comparison, the tertiary amine analogue 5 was found not to accumulate in heart tissue, to be an equally effective free-radical scavenger in vitro, but to require a higher dose to reduce infarct size in rats. This shows that the cardioselectivity of compound 1 contributes to its potency in salvaging myocardial tissue in rats after ischemia and reperfusion.
Grisar
J M
JM
Merrell Dow Research Institute, Strasbourg, France.
Petty
M A
MA
Bolkenius
F N
FN
Dow
J
J
Wagner
J
J
Wagner
E R
ER
Haegele
K D
KD
De Jong
W
W
D000818:Animals; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002317:Cardiovascular Agents / Q000138:chemical synthesis*; D016166:Free Radical Scavengers; D007202:Indicators and Reagents; D015227:Lipid Peroxidation / Q000187:drug effects; D015394:Molecular Structure; D009203:Myocardial Infarction / Q000188:drug therapy*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D051381:Rats; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014810:Vitamin E / Q000031:analogs & derivatives*
D001578:Benzopyrans; D002317:Cardiovascular Agents; D016166:Free Radical Scavengers; D007202:Indicators and Reagents; C064728:MDL 74270; C067190:MDL 73404; D014810:Vitamin E