吡唑并[1,5-a]嘧啶作为优势骨架在别构调节剂中的应用进展

Advances in Application of Pyrazolo[1,5-a]pyrimidine as Privileged Scaffold in Allosteric Modulators

针对靶蛋白别构位点开发的别构调节剂具有较高的选择性和较低的脱靶效应,一定程度上可克服正构药物导致的耐药问题,是目前小分子创新药物研发的重要策略之一。吡唑并[1,5-a]嘧啶作为嘌呤的生物电子等排体,是药物研发中一类重要的杂环优势骨架,广泛应用于抗肿瘤、抗感染、抗炎以及治疗中枢神经系统疾病等药物的研发中。该文综述了吡唑并[1,5-a]嘧啶作为优势骨架在别构调节剂中的应用及其构效关系研究,旨在为别构调节剂的筛选和优化提供参考。

Modulating protein function via targeting the allosteric binding sites is an essential strategy for smallmolecule drug development.Allosteric modulators show higher selectivity and lower off-target toxicity than orthosteric modulators,and thus have the potential to combat drug-resistant mutations at the orthosteric sites.Pyrazolo[1,5-a]-pyrimidine,a bioisostere of purine,is an important heterocyclic privileged scaffold in drug development.In recent years,pyrazolo[1,5-a]pyrimidine has been widely explored as a core skeleton in developing antitumor,anti-infective,antiinflammatory,and central nervous system agents.This review summarizes the latest application of pyrazolo[1,5-a]pyrimidine as a privileged scaffold in allosteric modulators and its structure-activity relationship,aiming to provide a reference and basis for screening and optimization of allosteric modulators.