Design and synthesis of novel phthalazinone derivatives as potent poly(ADP-ribose)polymerase 1 inhibitors

被引：8
作者：
Xin, Minhang [1 ]
Sun, Jiajia [1 ]
Huang, Wei [2 ]
Tang, Feng [3 ]
Liu, Zhaoyu [3 ]
Jin, Qiu [3 ]
Wang, Jia [3 ]
机构：
[1] Xi An Jiao Tong Univ, Hlth Sci Ctr, Sch Pharm, Dept Med Chem, 76 Yanta West Rd, Xian 710061, Peoples R China
[2] Cent China Normal Univ, Coll Chem, Int Joint Res Ctr Intelligent Biosensor Technol &, Key Lab Pesticide & Chem Biol,Minist Educ, Wuhan 430079, Peoples R China
[3] Jiangsu Simcere Pharmaceut Co Ltd, 699-18 Xuan Wu Dist, Nanjing 210042, Peoples R China
来源：
FUTURE MEDICINAL CHEMISTRY | 2020年 / 12卷 / 19期
关键词：
lead compound; PARP-1; inhibitors; phthalazinone derivatives; potent; sensitizing effect; PARP INHIBITORS; DNA-REPAIR; OPPORTUNITIES; DISCOVERY; THERAPY; UPDATE;
D O I：
10.4155/fmc-2020-0009
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
Aim:The development of effective PARP-1 inhibitors has received great enthusiasm in medicinal chemistry communities.Results:A new series of novel phthalazinone derivatives were designed and synthesized. Among these,B1andB16displayed more potent PARP-1 inhibitory activities than olaparib.B16gave an IC(50)value of 7.8 nM against PARP-1, and a PF(50)value of 3.4 in the sensitizing effect assay. Thein vivopharmacokinetic properties evaluation showedB16displayed insufficient oral exposure, and it was also not stable in rat blood.Conclusion:The results indicated that our design phthalazinone derivatives were potent PARP-1 inhibitors, and compoundB16was a valuable lead compound with siginificantin vitroefficacy, deseaving further optimization so as to develop anticancer drug candidate.
引用
收藏
页码：1691 / 1707
页数：17
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