新型取代的三唑并[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。
Design, synthesis, crystallographic studies, and preliminary biological appraisal of new substituted triazolo[4,3-b]pyridazin-8-amine derivatives as tankyrase inhibitors.
机构信息
Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia , Via del Liceo 1, 06123 Perugia, Italy.
出版信息
J Med Chem. 2014 Mar 27;57(6):2807-12. doi: 10.1021/jm401356t. Epub 2014 Feb 24.
Abstract
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.
摘要
为了寻找选择性的 Tankyrases（TNKSs）抑制剂，我们合成并生物学表征了一系列新型的 6,8-二取代的三唑并[4,3-b]哒嗪。基于结构的优化起始命中化合物 NNL（3）促使我们发现了 4-(2-(6-甲基-[1,2,4]三唑并[4,3-b]哒嗪-8-基氨基)乙基)苯酚（12），这是一种低纳摩尔选择性的 TNKSs 抑制剂，通过晶体结构分析确证其作为 NAD 类似物发挥作用。初步的生物学数据表明，这类新型衍生物是揭示 TNKS 在生理病理条件下的重要性的有力的药理学工具。
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