Tang Kai, Wang Shu, Gao Wenshuo, Song Yihui, Yu Bin
School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
Acta Pharm Sin B. 2022 Dec;12(12):4309-4326. doi: 10.1016/j.apsb.2022.09.022. Epub 2022 Oct 7.
The design of new ligands with high affinity and specificity against the targets of interest has been a central focus in drug discovery. As one of the most commonly used methods in drug discovery, the cyclization represents a feasible strategy to identify new lead compounds by increasing structural novelty, scaffold diversity and complexity. Such strategy could also be potentially used for the follow-on drug discovery without patent infringement. In recent years, the cyclization strategy has witnessed great success in the discovery of new lead compounds against different targets for treating various diseases. Herein, we first briefly summarize the use of the cyclization strategy in the discovery of new small-molecule lead compounds, including the proteolysis targeting chimeras (PROTAC) molecules. Particularly, we focus on four main strategies including fused ring cyclization, chain cyclization, spirocyclization and macrocyclization and highlight the use of the cyclization strategy in lead generation. Finally, the challenges including the synthetic intractability, relatively poor pharmacokinetics (PK) profiles and the absence of the structural information for rational structure-based cyclization are also briefly discussed. We hope this review, not exhaustive, could provide a timely overview on the cyclization strategy for the discovery of new lead compounds.
设计对目标靶点具有高亲和力和特异性的新型配体一直是药物研发的核心重点。作为药物研发中最常用的方法之一，环化反应通过增加结构新颖性、骨架多样性和复杂性，代表了一种识别新先导化合物的可行策略。这种策略也有可能用于后续药物研发而不侵犯专利。近年来，环化策略在发现针对不同靶点治疗各种疾病的新先导化合物方面取得了巨大成功。在此，我们首先简要总结环化策略在发现新的小分子先导化合物（包括蛋白酶靶向嵌合体（PROTAC）分子）中的应用。特别地，我们重点介绍四种主要策略，包括稠环化、链环化、螺环化和大环化，并强调环化策略在先导化合物生成中的应用。最后，还简要讨论了包括合成难度大、药代动力学（PK）特性相对较差以及缺乏基于合理结构的环化结构信息等挑战。我们希望这篇综述（虽不详尽）能够及时概述用于发现新先导化合物的环化策略。
