ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Curr Med Chem. 2012;19(23):3982-99. doi: 10.2174/092986712802002491.
Dipeptidyl peptidase 4 (DPP-4), a substrate-specific serine protease, has been validated as a promising drug target for the treatment of type 2 diabetes. DPP-4 inhibitors significantly lowered blood glucose levels in patients with type 2 diabetes without common body weight gain, hypoglycemia and gastrointestinal disturbance side effects. Therefore, DPP-4 inhibitors attracted more and more attention. In particular, non-peptidomimetic DPP-4 inhibitors have been a focus of research and development and made great progress in recent years, which resulted in the discovery of a wide variety of potent non-peptidomimetic DPP-4 inhibitors. Some of them, such as sitagliptin, alogliptin and linagliptin have already been used as marketed drugs, while others have been into clinical trials. Based on the core structural features of non-peptidomimetic DPP-4 inhibitors, seven types were classified in the article. For each type, we focused on the description of strategies for design and optimization, together with a discussion on concluded structure-activity relationships (SAR). In addition, the contribution of specific substituents to the inhibition of DPP-4 was summarized. Selectivity towards the inhibition of DPP-4 over dipeptidyl peptidase 8 (DPP-8) and dipeptidyl peptidase 9 (DPP-9) was also presented.
二肽基肽酶 4（DPP-4）是一种底物特异性丝氨酸蛋白酶，已被验证为治疗 2 型糖尿病的有前途的药物靶标。DPP-4 抑制剂可显著降低 2 型糖尿病患者的血糖水平，而不会引起常见的体重增加、低血糖和胃肠道紊乱等副作用。因此，DPP-4 抑制剂引起了越来越多的关注。特别是，非肽类 DPP-4 抑制剂一直是研究和开发的重点，并在近年来取得了很大进展，发现了多种有效的非肽类 DPP-4 抑制剂。其中一些，如西他列汀、阿格列汀和利格列汀已被用作上市药物，而其他药物则已进入临床试验。本文基于非肽类 DPP-4 抑制剂的核心结构特征，将其分为七类。对于每一种类型，我们重点介绍了设计和优化的策略，并讨论了总结的构效关系（SAR）。此外，还总结了特定取代基对 DPP-4 抑制作用的贡献。对 DPP-4 的抑制选择性与二肽基肽酶 8（DPP-8）和二肽基肽酶 9（DPP-9）的抑制选择性也进行了介绍。
