基于骨架跃迁和药物拼接所确立的新型二肽基肽酶IV抑制剂

A novel dipeptidyl peptidase IV inhibitors developed through scaffold hopping and drug splicing strategy

摘要: 截至目前，已有7个二肽基肽酶IV（DPP-IV）抑制剂成为抗糖尿病新药，它们的结构差异和内在关联性为进一步的结构修饰提供了新的思路。本研究针对阿格列汀和利那列汀的结构特征，采用骨架跃迁及药物拼接的原理，快速得到了新型的DPP-IV抑制剂8g（IC₅₀ = 4.9 nmol·L^-1），其活性和选择性均接近于上市新药。因此，运用经典的药物化学策略，对基于同一靶标的上市药物实施分子操作，可以有效地产生新型的活性分子。

Abstract: Though all the marketed drugs of dipeptidyl peptidase IV inhibitors are structurally different, their inherent correlation is worthy of further investigation. Herein we rapidly discovered a novel DPP-IV inhibitor 8g (IC₅₀ = 4.9 nmol·L^-1) which exhibits as good activity and selectivity as the market drugs through scaffold hopping and drug splicing strategies based on alogliptin and linagliptin. This study demonstrated that the employment of classic medicinal chemistry strategy to the marketed drugs with specific target is an efficient approach to discover novel bioactive molecules.