METABOLISM OF PYRUVATE ESTERS AND THIOESTERS

描述：已经合成了许多丙酮酸酯和硫酯。 合成并显示出潜在的用于预防和治疗 再灌注损伤，还用于预防肝乙醇毒性， 以药理学剂量给药。在这个项目中，研究人员将 测试二丙酰-乙酰甘油（DPAG）、二丙酰-乙酰- 二羟基丙酮（PADA）和丙酮酸N-乙酰半胱氨酸乙酯（PNACE） 可以输送治疗水平的丙酮酸而不引起乳酸酸中毒 和钠超载临床前研究将进行：1）规模 这些化合物的合成和制备新的类似物， 2）表征这些化合物的代谢和药效学 化合物在大鼠、狗和猪中的作用; 3）确定 丙酮酸酯和硫酯的心脏保护作用是结果 从I）回补，如果柠檬酸循环中间体，和ii）抑制 通过增加丙二酰辅酶A的脂肪酸氧化;和4）表征 在给予乙醇的大鼠和狗中， 硫酯对乙醇氧化的影响，中间代谢的扰动 和自由基的产生。

DESCRIPTION: A number of pyruvate esters and thioesters have been synthesized and shown to be potentially useful in preventing and treating reperfusion injury and also for preventing hepatic ethanol toxicity when given in pharmacological doses. In this project, the investigators will test the hypothesis that dipruvyl-acetyl glycerol (DPAG), pyruvyl-acetyl- dihydroxyacetone (PADA), and pyruvate N-acetylcysteine ethyl ester (PNACE) can deliver therapeutic levels of pyruvate without causing lactic acidosis and sodium overload. Preclinical studies will be carried out: 1) to scale up the synthesis of these compounds and prepared new analogs of these compounds; 2) to characterize the metabolism and pharmacodynamics of these compounds in rats, dogs and swines; 3) to determine if the cardioprotective effect of pyruvate esters and thioesters are the result from I) anaplerosis if citric acid cycle intermediates, and ii) inhibition of fatty acid oxidation via increased malonyl-CoA; and 4) to characterize in rats and dogs given ethanol, the effect of pyruvate esters and thioesters on ethanol oxidation, perturbation of intermediary metabolism and free radical production.