设计和合成 2-(4,5,6,7-四氢噻吩并[2,3-d]嘧啶-2-基)-苯并咪唑甲酰胺类新型口服有效的聚(ADP-核糖)聚合酶(PARP)抑制剂。
Design and synthesis of 2-(4,5,6,7-tetrahydrothienopyridin-2-yl)-benzoimidazole carboxamides as novel orally efficacious Poly(ADP-ribose)polymerase (PARP) inhibitors.
机构信息
Synthetic Organic & Medicinal Chemistry Laboratory, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
出版信息
Eur J Med Chem. 2018 Feb 10;145:389-403. doi: 10.1016/j.ejmech.2018.01.018. Epub 2018 Jan 8.
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 IC of 18 nM and 42 nM, respectively. Furthermore, it can selectively kill BRCA2 deficient V-C8 cells with a CC 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.
聚（ADP-核糖）聚合酶-1/2（PARP-1/2）是核蛋白，参与内源性或外源性过程引起的 DNA 修复。在过去十年中，PARP-1/2 抑制剂已被证明对 DNA 修复缺陷的肿瘤具有临床疗效。我们开发了一系列 4,5,6,7-四氢噻吩并吡啶-2-基苯并咪唑甲酰胺作为新型有效的 PARP-1/2 抑制剂。该系列中效果最好的化合物是化合物 27，其对 PARP-1 和 PARP-2 的抑制活性分别为 18 nM 和 42 nM，IC 分别为 18 nM 和 42 nM。此外，它可以选择性地杀死 BRCA2 缺陷的 V-C8 细胞，CC 为 920 nM。在 MDA-MB-436（BRCA-1 突变）异种移植模型中，该化合物具有良好的耐受性并显示出单药活性。基于上述结果，化合物 27 已被选为针对 PARP-1/2 的候选药物，其临床前特征也正在进行中。
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