3-Hydroxy-alpha-methyltyrosine progenitors: synthesis and evaluation of some (2-oxo-1,3-dioxol-4-yl)methyl esters.
The (5-methyl-2-oxo-1,3- dioxol -4-yl)methyl and (5-tert-butyl-2-oxo-1, 3- dioxol -4-yl)methyl esters of 3-hydroxy-alpha-methyltyrosine (methyldopa) were prepared and evaluated as progenitors of the amino acid. 1H NMR experiments reveal that the esters are converted cleanly to methyldopa and the corresponding alpha-diketone at pH 7.4, with the 5-methyl derivative undergoing hydrolysis faster than the 5-tert-butyl analogue. Bioavailability studies in dogs show that the esters, particularly the 5-methyl derivative, yield significant plasma levels of methyldopa. Both esters are orally effective antihypertensive agents in spontaneously hypertensive (SH) rats. These studies indicate that (2-oxo-1,3- dioxol -4-yl)methyl esters are viable prodrugs for the latentiation of methyldopa.
D000818:Animals; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D004149:Dioxoles / Q000138:chemical synthesis* / Q000378:metabolism; D004285:Dogs; D008297:Male; D008750:Methyldopa / Q000378:metabolism*; D051381:Rats
D004149:Dioxoles; D008750:Methyldopa