Design and synthesis of 2-(4,5,6,7-tetrahydrothienopyridin-2-yl)-benzoimidazole carboxamides as novel orally efficacious Poly(ADP-ribose)polymerase (PARP) inhibitors

被引：46

作者：

Chen, Xuxing ^{[1
,2
]}

Huan, Xiajuan ^{[3
]}

Liu, Qiufeng ^{[2
,4
]}

Wang, Yuqin ^{[1
]}

He, Qian ^{[1
]}

Tan, Cun ^{[1
]}

Chen, Yi ^{[3
]}

Ding, Jian ^{[3
]}

Xu, Yechun ^{[4
]}

Miao, Zehong ^{[3
]}

Yang, Chunhao ^{[1
]}

机构：

[1] Chinese Acad Sci, Shanghai Inst Mat Med, Synthet Organ & Med Chem Lab, State Key Lab Drug Res, Shanghai 201203, Peoples R China

[2] Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China

[3] Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China

[4] Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 145卷

基金：

中国国家自然科学基金;

关键词：

PARP1/2; inhibitor; Benzimidazole; 4,5,6,7-Tetrahydrothienopyridine; Co-crystal structure; Isothermal Titration Calorimetry; CANCER-THERAPY; POLYMERASE INHIBITORS; BIOLOGICAL EVALUATION; ANTICANCER ACTIVITY; EXCISION-REPAIR; CELLS; TARGETS; CYTOTOXICITY; ACTIVATION; BINDING;

D O I：

10.1016/j.ejmech.2018.01.018

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The nuclear protein poly(ADP-ribose) polymerases-1/2 (PARP-1/2) are involved in DNA repair damaged by endogenous or exogenous process. And PARP-1/2 inhibitors have been proved to be clinically efficacious for DNA repair deficient tumors in the past decade. We have developed a series of 4,5,6,7-tetrahydrothienopyridin-2-yl benzimidazole carboxamides as novel and potent PARP-1/2 inhibitors. The best compound resulted from this series is compound 27 which displays excellent PARP-1 and PARP-2 inhibitory activity with IC50 of 18 nM and 42 nM, respectively. Furthermore, it can selectively kill BRCA2 deficient V-C8 cells with a CC50 of 920 nM. In the MDA-MB-436 (BRCA-1 mutant) xenograft model, this compound was well tolerated and showed single-agent activity. Based on the results above, compound 27 has been selected as a lead candidate targeting PARP-1/2 and its preclinical characterization is also underway. (C) 2018 Elsevier Masson SAS. All rights reserved.

引用

页码：389 / 403

页数：15

共 39 条

[31] DNA strand breakage, activation of poly(ADP-ribose) synthetase, and cellular energy depletion are involved in the cytotoxicity in macrophages and smooth muscle cells exposed to peroxynitrite [J].