降血糖药物普兰林肽的固相合成.pdfVIP

附 图··························································································· ···············23 附 表··························································································· ···············36 讨 论··························································································· ···············42 结 论··························································································· ···············43 参考文 献··························································································· ·······45 综 述··························································································· ···············47 致 谢··························································································· ···············54 个人简 历··························································································· ···············55 中 文 摘 要 降血糖药物普兰林肽的固相合成 摘 要 世界卫生组织统计数据表明，全球糖尿病患者已超过3.6 亿人，我国 糖尿病患者人数居世界第一，现有降糖药物种类较多，降糖机制不尽相同， 但是仍不能满足临床用药的需要。2005 年 3 月，FDA 批准普兰林肽 （Pramlintide ）注射剂用于成人1 型和2 型糖尿病，并取得良好的临床效 [1] 果。普兰林肽是1 型和2 型糖尿病的辅助 治疗药物，主要用于单用某种 降糖药物不起作用的糖尿病患者，它辅助降糖药物形成一种人体内环境， [2] 使其发挥降糖作用。此外，有研究报道，普兰林肽还具有调节食欲 的作 用，美国Amylin 制药公司正在利用普兰林肽开发减肥药。国内报道，黄 [3] 亚东等人采用基因方法 合成了一种改构的人淀粉样多肽突变体-普兰林 肽；近年来，国内外有关普兰林肽固相合成研究较多，主要集中在片段合 [4] 成 。总体看来，降糖药物普兰林肽注射剂给特殊糖尿病患者带来了福音， 但进口普兰林肽价格昂贵，且难以满足国内市场的需求，随着普兰林肽在 糖尿病中治疗地位日趋重要，开发国产普兰林肽原料药的合成工艺研究具 有重要的意义。 [5] 普兰林肽含 37 个氨基酸以及一对二硫键 。药理研究表明，普兰林 肽的 1-22 个氨基酸及分子内二硫键，末端酰胺是其重要的分子生物学功 [6] 能位点 ，也是合成过程中需要关键注意的氨基酸位点。本研究采用Fmoc 固相多肽合成法，采用逐步缩合的策略，以Rink Amide-AM 树脂做载体， HBTU-HOBt-DIEA 做缩合剂，得到全保护线性普兰林