2-(1-丙基哌啶-4-基)-3H-咪唑并[4,5-c]吡啶-7-甲酰胺的发现与构效关系研究：一种用于治疗癌症的聚（ADP-核糖）聚合酶-1（PARP-1）强效抑制剂
Discovery and SAR study of 2-(1-propylpiperidin-4-yl)-3H-imidazo[4,5-c]pyridine-7-carboxamide: A potent inhibitor of poly(ADP-ribose) polymerase-1 (PARP-1) for the treatment of cancer.
作者信息
Zhu Qihua, Wang Xueyan, Hu Yan, He Xiaorong, Gong Guoqing, Xu Yungen
机构信息
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 21009, China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 21009, China.
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 21009, China.
出版信息
Bioorg Med Chem. 2015 Oct 15;23(20):6551-9. doi: 10.1016/j.bmc.2015.09.026. Epub 2015 Sep 16.
A series of imidazo[4,5-c]pyridine-7-carboxamide derivatives as poly(ADP-ribose) polymerase (PARP) inhibitors have been developed. All target compounds were evaluated for their PARP-1 inhibitory activity and some were further assessed for cellular potency. These efforts led to identification of a novel PARP-1 inhibitor 2-(1-propylpiperidin-4-yl)-3H-imidazo[4,5-c]pyridine-7-carboxamide 11a (XZ-120312). 11a displayed strong inhibition against the PARP-1 enzyme with an IC50 of 8.6±0.6 nM and excellent potentiation of temozolomide cytotoxicity in cancer cell lines SW-620, MDA-MB-468 and A549 by 4.0, 3.0 and 7.7 times, respectively.
已经开发出一系列作为聚（ADP - 核糖）聚合酶（PARP）抑制剂的咪唑并[4,5 - c]吡啶 - 7 - 甲酰胺衍生物。对所有目标化合物进行了PARP - 1抑制活性评估，对其中一些化合物进一步评估了细胞活性。这些研究工作导致鉴定出一种新型PARP - 1抑制剂2 - （1 - 丙基哌啶 - 4 - 基） - 3H - 咪唑并[4,5 - c]吡啶 - 7 - 甲酰胺11a（XZ - 120312）。11a对PARP - 1酶表现出强烈抑制作用，IC50为8.6±0.6 nM，并且在癌细胞系SW - 620、MDA - MB - 468和A549中分别将替莫唑胺的细胞毒性增强了4.0倍、3.0倍和7.7倍。
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