Identification of 2-substituted pyrrolo[1, 2-b]pyridazine derivatives as new PARP-1 inhibitors. (1st January 2021)

• Record Type: Journal Article
• Authors: Xiang, Hao-Yue; Chen, Jian-Yang; Huan, Xia-Juan; Chen, Yi; Gao, Zhao-bing; Ding, Jian; Miao, Ze-Hong; Yang, Chun-Hao
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 31(2021)
• Publication Date: 2021-01-01
• Subjects: Antiproliferative -- Cancer -- PARP inhibitors -- Pyrrolo[12-b]pyridazine; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2020.127710
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: A library of new 2-substituted pyrrolo[1, 2- b ]pyridazine derivatives were rapidly assembled and identified as PARP inhibitors. Structure-activity relationship for this class of inhibitor resulted in the discovery of most potent compounds 15a and 15b that exhibited about 29- and 5- fold selective activity against PARP-1 over PARP-2 respectively. The antiproliferative activity of the as-prepared compounds were demonstrated by further celluar assay in BRCA2-deficient V-C8 and BRCA1-deficient MDA-MB-436 cell lines, displaying that compound 15b could robustly reduce the corresponding cell proliferation and growth with CC50 s of 340 and 106 nM respectively. The PK property of 15b was also investigated here.