Harnessing the cyclization strategy for new drug discovery  

作　　者：Kai Tang Shu Wang Wenshuo Gao Yihui Song Bin Yu 

机构地区：[1]School of Pharmaceutical Sciences,Zhengzhou University,Zhengzhou 450001,China

出　　处：《Acta Pharmaceutica Sinica B》2022年第12期4309-4326,共18页药学学报（英文版）

基　　金：This work is supported by the National Natural Science Foundation of China(Nos.22277110,81973177 and 31900875,China);the Natural Science Foundation of Henan Province(Nos.222300420069 and 222301420049,China);Program for Science&Technology Innovation Talents in Universities of Henan Province(No.21HASTIT045,China).

摘　　要：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.

关 键 词：Ring cyclization SPIROCYCLIZATION MACROCYCLIZATION Conformational constraint Lead generation New drug discovery 

分 类 号：R91[医药卫生—药学]