糖原磷酸化酶(GP)抑制剂作为潜在的新型抗糖尿病药物，其特点是具有葡萄糖浓度依赖性的降糖效应，该优点可有效避免低血糖不良反应的发生。因此，开发GP抑制剂具有重要的临床意义。本研究前期发现了具有苯并氧氮杂卓酮结构的GP抑制剂Qin74，其酶抑制活性达到纳摩尔级别且与葡萄糖浓度呈明显的依赖关系，在体内药效学评价中也表现出优异的降糖活性。本项目拟结合经典药物设计和计算机辅助药物设计的方法，进行先导化合物的结构优化，再从分子、细胞和动物三个水平对优化化合物进行活性评价。此基础上，针对GP抑制剂缺乏选择性易导致肌毒性的问题，以前期研究发现的新型GP抑制剂Qin74及结构优化后的优选化合物为母药，创新性的设计兼具肝脏靶向输送和定位释放双功能的GP抑制剂肝靶向前药，拟获得结构骨架新、靶向效率高、降糖活性好的靶向前药分子。该工作一方面为GP抑制剂的临床开发奠定基础，一方面为降糖药物的研究提供新的研发思路。

Glycogen phosphorylase inhibitors, which have been regarded as potent therapeutic agents for type 2 diabetes, display hypoglycemic activity in a glucose-dependent manner. This benefit can effectively avoid adverse hypoglycemic events. Therefore, discovery and development of GP inhibitors plays a significant role in the treatment of diabetes. We recently developed a highly potent GP inhibitor Qin74, which showed nanomolar inbibitory activity synergistically with glucose. Compound Qin74 also exhibited significant activity in lowering blood glucose level in diabetic rats. In this study, based on the chemical structure of lead compound Qin74, rational structural optimization was carried out. First, a combination approach of traditional medicinal chemistry and modern drug design technique is applied to design new compounds. Next, these compounds are assayed for their activities at molecular, cellular, and animal levels. Finally, in order to reduce the risk of myopathy caused by GP inhibitors, a series of liver-targeted prodrugs that can be used to deliver GP inhibitors to liver tissue and release the bioactive content in liver, will be designed and synthesized by using the highly potent GP inhibitors as substrates. Some novel prodrugs with high activity and liver specificity will be obtained from this project. We will not only establish the foundation for clinical application of GP inhibitors, but also develop a novel research idea and practice on study of antidiabetic agents from this work.