3-Hydroxy-.alpha.-methyltyrosine progenitors, synthesis and evaluation of some (2-oxo-1,3-dioxol-4-yl)methyl esters
| Autor: | Walfred S. Saari, D. W. Cochran, M. R. Dobrinska, S. L. Gaul, D. C. Titus, Wasyl Halczenko, C. S. Sweet, W. C. Vincek |
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| Rok vydání: | 1984 |
| Předmět: |
Male
chemistry.chemical_classification Stereochemistry Biological Availability Blood Pressure Biological activity Dioxoles Prodrug Rats Bioavailability Amino acid chemistry.chemical_compound Hydrolysis Dogs chemistry Drug Discovery medicine Animals Molecular Medicine Alpha-Methyltyrosine Methyldopa cardiovascular diseases Derivative (chemistry) medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 27:713-717 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm00372a002 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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