DEAZA ANALOGS OF ALDOSE REDUCTASE INHIBITORS

描述（研究者摘要）：糖尿病并发症，如 白内障形成、视网膜病和神经病被认为是由 高细胞内山梨醇浓度。由于醛糖还原酶催化 过量的葡萄糖转化为山梨糖醇，抑制这种酶 代表临床上有用的治疗方法和/或 预防这些并发症。 虽然有大量的化合物 被发现能抑制这种酶，只有少数几种足够有效， 临床试验研究。 因此，需要更有效的 酶的抑制剂。 一种亲核氨基酸，能够可逆地 与醛糖还原酶抑制剂的相互作用已经在 抑制剂结合位点。 调查人员的目标是（a） 通过C-13 NMR研究研究， 通过使用富含C-13的抑制剂发生酶及其抑制剂;和（B） 研究增加醛糖还原酶抑制剂的反应性 对亲核攻击的抑制活性将增加 抑制剂.为了验证上述假设，希望开发有效的 醛糖还原酶抑制剂，本提案的目的是：（1）设计 与已知的醛糖还原酶抑制剂Alconil相关的化合物， 山梨腈，但处理亲电性更强的反应中心（如 α，β-不饱和体系）;（2）合成如此设计的化合物; 和（3）测定抑制大鼠透镜醛糖的IC 50值 还原酶的这些化合物和为alconil和sorbinil，并比较 这些值来确定哪一种是酶的更好的抑制剂。 的 从长远来看，这项研究中最有效的化合物将在 体内使用糖尿病大鼠模型，以确定它们在糖尿病中的有效性。 预防和/或治疗糖尿病并发症。 从这些 研究将增加关于结构活性关系的现有数据 的醛糖还原酶，因此作为指导，在未来的设计 新的醛糖还原酶抑制剂。

DESCRIPTION (Investigator's Abstract): Diabetic complications such as cataract formation, retinopathy, and neuropathy are believed to result from high intracellular sorbital concentrations.Since aldose reductase catalyzes the conversion of excess glucose to sorbitol, inhibition of this enzyme represents a clinically useful approach toward the treatment and/or prevention of these complications. Though a large number of compounds have been found to inhibit the enzyme, only a few are potent enough to warrant clinical trial studies. There is therefore the need for more potent inhibitors of the enzyme. A nucleophilic amino acid capable of reversible interactions with aldose reductase inhibitors has been identified at the inhibitor binding site. It is the investigators objective to (a) investigate by C-13 NMR studies if a nucleophilic interaction between the enzyme and its inhibitor occurs by using a C-13 enriched inhibitor; and (b) investigate if increasing the reactivity of an aldose reductase inhibitor towards nucleophilic attack would increase the inhibitory activity of the inhibitor. To test the above hypothesis with the hope of developing potent aldose reductase inhibitors, it is the aim of this proposal to: (1) design compounds related to the known aldose reductase inhibitors alconil and sorbinil but processing electrophilically more reactive centers (such as alpha, beta-unsaturated systems); (2) synthesize the compounds so designed; and (3) determine the IC50 values for the inhibition of rat lens aldose reductase for these compounds and for alconil and sorbinil, and compare these values to determine which is a better inhibitor of the enzymes. The most potent compounds from this study will, in the long-term, be studied in vivo using a diabetic rat model to determine their effectiveness in the prevention and/or treatment of diabetic complications. Results from these studies will add to available data on the structure activity relationships of aldose reductase and hence serve as a guide in the future design of novel aldose reductase inhibitors.