Searching for selective tankyrases (TNKSs) inhibitors, a new small series of 6,8-disubstituted triazolo[4,3-b]piridazines has been synthesized and characterized biologically. Structure-based optimization of the starting hit compound NNL (3) prompted us to the discovery of 4-(2-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-8-ylamino)ethyl)phenol (12), a low nanomolar selective TNKSs inhibitor working as NAD isostere as ascertained by crystallographic analysis. Preliminary biological data candidate this new class of derivatives as a powerful pharmacological tools in the unraveling of TNKS implications in physiopathological conditions.

中文翻译：

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新型取代三唑并[4,3-b]哒嗪-8-胺衍生物作为端锚聚合酶抑制剂的设计、合成、晶体学研究和初步生物学评价

为寻找选择性端锚聚合酶 (TNKS) 抑制剂，合成并表征了一系列新的 6,8-二取代三唑并 [4,3- b ] 哌哒嗪。起始命中化合物 NNL ( 3 )的基于结构的优化促使我们发现了 4-(2-(6-methyl-[1,2,4]triazolo[4,3 - b ]pyridazin-8-ylamino)乙基)苯酚 ( 12 )，一种低纳摩尔选择性 TNKS 抑制剂，作为 NAD 等排体，通过晶体分析确定。初步生物学数据表明，这类新衍生物是揭示 TNKS 对病理生理条件影响的强大药理学工具。