作者:Thomas D. Aicher、Gregory R. Bebernitz、Philip A. Bell、Leonard J. Brand、Jeremy G. Dain、Rhonda Deems、William S. Fillers、James E. Foley、Douglas C. Knorr、Jeffrey Nadelson、Dario A. Otero、Ronald Simpson、Robert J. Strohschein、Douglas A. Young
DOI:10.1021/jm980438y
日期:1999.1.1
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-hydroxy propyl)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 mu mol/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 mu mol/kg/day. 14b was selected for clinical studies.