METABOLISM OF PYRUVATE ESTERS AND THIOESTERS

描述：一些丙酮酸酯和硫代酯已被 合成的，并被证明在预防和治疗方面潜在有用 再灌流损伤，也用于预防肝脏乙醇中毒时 以药理剂量给药。在这个项目中，调查人员将 检验假设，丙酮酰-乙酰甘油(DPAG)，丙酮-乙酰甘油- 二羟基丙酮(PADA)和丙酮酸N-乙酰半胱氨酸乙酯(PNACE) 可以提供治疗水平的丙酮酸而不会导致乳酸酸中毒 和钠超载。将开展临床前研究：1)规模化 加快了这些化合物的合成，并准备了这些化合物的新类似物 化合物；2)表征这些化合物的代谢和药效学。 大鼠、狗和猪体内的化合物；3)确定 丙酮酸酯和硫代酯的心脏保护作用是结果 来自i)柠檬酸循环中间体的抑制，以及ii)抑制 通过增加丙二酰辅酶A的脂肪酸氧化；以及4)表征 在给予乙醇的大鼠和狗身上，丙酮酸酯和 硫代酯类化合物对乙醇氧化、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.