| Autor: |
Aicher, T. D., Bebernitz, G. R., Bell, P. A., Brand, L. J., Dain, J. G., Deems, R., Fillers, W. S., Foley, J. E., Knorr, D. C., Nadelson, J., Otero, D. A., Simpson, R., Strohschein, R. J., Young, D. A. |
| Zdroj: |
Journal of Medicinal Chemistry; January 14, 1999, Vol. 42 Issue: 1 p153-163, 11p |
| Abstrakt: |
SAH 51-641 (1) is a potent hypoglycemic agent, which acts by inhibiting hepatic gluconeogenesis. It is a prodrug of 4-(2,2-dimethyl-1-oxopropyl)benzoic acid (2) and 4-(2,2-dimethyl-1-hydroxypropyl)benzoic acid (3), which sequester coenzyme A (CoA) in the mitochondria, and inhibits medium-chain acyltransferase. 1−3 and 4-tert-butylbenzoic acid all cause testicular degeneration in rats at pharmacologically active doses. 14b (FOX 988) is a prodrug of 3, which is metabolized in the liver at a rate sufficient enough to have hypoglycemic potency (an ED50 of 65 μmol/kg, 28 mg/kg/day, for glucose lowering), yet by avoiding significant escape of the metabolite 3 to the systemic circulation, it avoids the testicular toxicity at doses up to 1500 μmol/kg/day. 14b was selected for clinical studies. |
| Databáze: |
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